Seamless Phase 2/Phase 3 Clinical Study to Assess the ...

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Seamless Phase 2/Phase 3 Clinical Study to Assess the Effect of Once-Daily Dosing With

Sustained-Effects Liothyronine (LT3) on Maintenance of Euthyroid Status in Patients

With Hypothyroidism

Running title: Sustained-Effects LT3 for Hypothyroidism Treatment

Corresponding Author:

Keith R. Latham, PhD.

ITL Pharma, Inc.

LIAS Campus, Building B

100 Coley Street

Kingsport, TN 37660

Phone: 423-444-1474

Email: [email protected]

2nd Author: 3rd Author:

Regina L Garland, MEd. George A. Corey, MD

Clinical Research Director Executive Director

LIAS Research University Health Services

100 Coley St, LIAS Campus Bldg A Univ. of Mass.,Amherst

Kingsport, TN 37660 Amherst, MA 01003

PHONE: 423-967-7378 PHONE: 413-577-5211

Email: [email protected] Email: [email protected]

ITL Pharma, Kingsport, TN, is the sponsor of these 505(b)(2) studies and holds the IND

(114322) for the sustained release T3 preparation used in this study (TriThroid®).

Keith R. Latham, PhD, is the inventor (US 9,526,701) and ITL Pharma is the owner and

manufacturer of TriThroid®, a proprietary name approved by FDA and USPTO for this product.

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ABSTRACT

Objective: The aim of this phase 2/phase 3 combined clinical trial was to determine whether

once-daily dosing with TriThroid® (LT3) can fully manage the symptoms of hypothyroidism

and replace levothyroxine-containing products as a monotherapy.

Methods: Eighteen patients taking levothyroxine (LT4) to manage hypothyroidism were

recruited for this trial. On day 1 of the 6-week study, all patients discontinued their LT4 dose and

initiated once-daily treatment with LT3 (TriThroid®) 15 mcg for 2 weeks. At week 3, patients

were provided with a week’s supply of LT3 30-mcg tablets (if the patient’s prestudy LT4 dose

was <100 mcg) or 45-mcg tablets (if the patient’s prestudy LT4 dose was ≥100 mcg). If any

patient had a thyroid-stimulating hormone (TSH) level >5 mIU/L 1 week after starting the 30- or

45-mcg dose, their daily dose was increased by 15 mcg at their next visit to a maximum dose of

60 mcg. Various assessments of thyroid status were performed weekly, and during the last 8

hours of week 6, hourly testing was initiated after the final LT3 dose to assess pharmacokinetic

parameters.

Results: T3 levels remained stable throughout the study (99.5 ± 22.9 ng/dL at baseline, 91.9 ±

40.2 ng/dL at 2 weeks, and 96.1 ± 32.2 ng/dL at 6 weeks). Mean serum TSH levels increased

from 1.56 ± 0.81 mIU/L at baseline to 5.90 ± 5.74 mIU/L at 2 weeks and decreased to 3.84 ±

3.66 mIU/L at 6 weeks. Total T4 and FT4 levels decreased once levothyroxine was discontinued

and LT3 treatment was initiated. Euthyroid symptoms and SF-36 Physical Component Scores

improved significantly during weeks 4 to 6 (P <0.04).

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Conclusions: Once-daily treatment with TriThroid®, at 30, 45, or 60 mcg (LT3) served as a

satisfactory therapeutic replacement for levothyroxine with respect to both hormone levels and

symptom scores.

Keywords: T3, triiodothyronine, T3 monotherapy, daily administration, seamless clinical trials,

sustained effects

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INTRODUCTION

Thyroxine, the most abundant thyroid hormone in the thyroid gland, was first isolated from the

gland in 19141 and was first economically synthesized in 1949.2 Triiodo-L-thyronine (LT3) was

not discovered until 1952,3,4 and the recognition that LT4 is an inactive pro-hormone for LT3

formation was not published until 1970.5,6 Thus, the use of synthetic thyroxine (LT4,

levothyroxine) rather than triiodo-L-thyronine (liothyronine) for the treatment of hypothyroidism

was a result of historic events rather than the result of scientific analysis of optimal therapeutic

efficacy.7 Based on this historic perspective, it is possible that thyroxine products would be of

only minor importance today if LT3 had been discovered first.

Problems With Thyroxine Products

Years of experience with levothyroxine products have revealed multiple problems with their use.

First, thyroxine is a pro-drug (pro-hormone) that is nearly inactive and must be enzymatically de-

iodinated to form 3,5,3'-triiodo-L-thyronine (LT3) for physiologic activity. It is estimated that

20% of patients with hypothyroidism cannot convert LT4 to LT3,and levothyroxine

monotherapy may be ineffective in this subset of patients.8

Second, iodothyronine compounds are chemically unstable. The current formulations of LT3

(Cytomel) and LT4 (eg, Synthroid, Unithroid, Euthyrox, Levoxyl), including generic products,

degrade over time, resulting in suboptimal dosing 18 and the accumulation of toxic contaminants

(mainly quinones19). This degradation is accelerated by oxygen, water, basic pH conditions, and

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ultraviolet exposure. Levothyroxine contains 11.3% water of crystallization (Na·5H20), and the

excipient products in the formulation also contribute more casually bound water (typically

approximately 2-5%)16 LT4 formulations are also contaminated with additional atmospheric

water and oxygen. In addition, Levothyroxine is purified as a monosodium salt by precipitation

from an aqueous solution of Na2CO3, leaving a residual high pH environment. As a result of

these combined conditions, products containing LT4 are generally filled at 105% of dose and

recalled at 95%, as degradation proceeds.

Finally, LT4 is poorly absorbed (42%-74%) from the digestive tract into the blood,12 and

absorption is highly variable depending on the pathophysiologic state of the patient.13

TriThroid®, a patented sustained-release/sustained-effects delivery system (ITL Pharma, US

9,526,701) containing LT3 as the active pharmaceutical ingredient, overcomes these

limitations.14 Because LT3 is the active hormone in TriThroid®, this formulation could fully

manage hypothyroidism in patients who do not adequately convert LT4 to LT3. In addition,

TriThroid® is produced as tablets that are devoid of water and oxygen, are pH adjusted, and are

prepared and packaged in anhydrous Argon, resulting in a product that is shelf-stable for more

than 3 years. LT3 from TriThroid® is more than 90% absorbed from the digestive system into

the blood, providing stable and consistent dosing, allowing for micromanagement of

hypothyroidism.

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Therapeutic Context for TriThroid®

It is difficult to determine the exact percentage of patients with hypothyroidism whose symptoms

are resistant or partially resistant to levothyroxine therapy. Overall, very few patients treated

with levothyroxine claim full recovery to pre-hypothyroid clinical status. One survey of

physicians prescribing T4 products for the management of hypothyroidism found that a

significant number (more than 20%) of patients have symptoms that are not effectively managed

by a full thyroid replacement dose of approximately 100 mcg/day and increasing the LT4 dose in

these patients does not improve their clinical status or overall well-being.8

Thus, it can be estimated that approximately 20% of patients with hypothyroidism have

symptoms that cannot be managed with thyroxine alone and may be candidates for TriThroid®

therapy.

The aim of this phase 2/phase 3 combined clinical trial was therefore to determine whether once-

daily dosing with TriThroid® (LT3) is bioequivalent to Synthroid (LT4) and can serve as a safe

and effective therapy for the management of hypothyroidism.

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METHODS

Participation Recruitment and Study Procedures

This study was approved by the Georgetown University Institutional Review Board and was

registered at ClinicalTrials.gov as clinical trial NCT01800617.

Participants aged 18 to 65 years with hypothyroidism of any etiology were recruited. Initial

screening involved a questionnaire that was administered over the telephone. Eligible patients

could have no diagnosed major medical problems (eg, cardiac disease, pulmonary conditions,

diabetes, malignancy) other than thyroid disease. Thyroid disease in all eligible study patients

was managed with an LT4 (Synthroid) dose of 75 mcg or greater to ensure that all included

participants had no significant depletion of thyroid function. Patients taking steroids, or any

medications known to affect thyroid hormone metabolism, thyroid hormone absorption, or

thyroxine-binding globulin were excluded. Women who were pregnant, lactating, or taking oral

contraceptives were also ineligible for the study.

Patients who appeared to be eligible for the study were scheduled for a visit to the Georgetown

Clinical Research Unit (GCRU); if they were determined to be eligible for study inclusion, they

signed a written informed consent form. Eligible patients were determined to be in general good

health based on the results of medical history, physical examination, 12-lead electrocardiogram

(ECG), and a screening thyroid-stimulating hormone (TSH) test. Women also underwent a

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screening pregnancy test. Participants were eligible if clinical laboratory testing showed that they

had a normal serum TSH level (0.4-4.5 mIU/L) when being treated with LT4.

On the first day of the study (baseline), the participants refrained from taking their usual LT4

tablet and reported to the GCRU in a fasting state, having not eaten since 10:00 pm the previous

day. Vital signs, including heart rate, systolic blood pressure, diastolic blood pressure,

respiratory rate, temperature, height, weight, and body mass index, were measured after the

patients had rested for a minimum of 5 minutes in a seated position. Metabolic parameters were

also documented; respiratory quotient and resting energy expenditure were measured using a

Vmax Encore Metabolic Cart. An ECG was obtained. Baseline thyroid function levels (TSH,

total thyroxine [T4], free thyroxine [FT4], total triiodo-L-thyronine [T3], free triiodo-L-

thyronine [FT3]) were measured, as well as the values of thyroid hormone-responsive

biochemical markers (lipid profile, sex hormone-binding globulin [SHBG], and ferritin).

Questionnaires regarding thyroid status and therapeutic preference for LT3 versus LT4 were

administered, and SF-36 Physical Component Score and Mental Component Score were

obtained. The participant was then given a week’s supply of LT3 15-mcg tablets and asked to

take this instead of their LT4 product.

All patients returned to the GCRU after 1 week (week 1). At this visit, all assessments were

repeated, and the participants were given another week’s supply of TriThroid® 15-mcg LT3

tablets.

All patients returned to the GCRU after another week (week 2), and all assessments were

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performed again. At this visit, patients were provided with a week’s supply of TriThroid®; if the

patient’s prestudy dose of LT4 was less than 100 mcg, the dose provided was 30 mcg; if the

patient’s prestudy dose of LT4 was 100 mcg or greater, the dose provided was 45 mcg LT3.

At each of the 4 subsequent weekly visits (weeks 3-6), all assessments were repeated and a

week’s supply of TriThroid® was provided. If any patient had a TSH level greater than 5 mIU/L

1 week after starting their 30- or 45-mcg dose, their daily dose was increased by 15 mcg LT3 at

their next visit, up to a maximum dose of 60 mcg LT3.

Pharmacokinetic Evaluation at Final Visit

At the final study visit (at the end of week 6), patients presented to the GCRU before taking their

daily LT3 dose. Baseline thyroid function levels (TSH, total T4, FT4, total T3, FT3) and

biochemical markers were assessed at 8:00 AM (time 0). The patient’s current dose of LT3, from

TriThroid®, was administered orally at approximately 8:05 AM with a glass of water. Thyroid

function levels (TSH, total T4, FT4, total T3, FT3) were assessed again 30 minutes after

TriThroid® administration, then at hourly intervals for 8 additional samples. Vital signs were

measured, and an ECG was obtained at 4 hour intervals. Light meals were provided at

approximately 9:30 AM and 12:00 PM. At the end of the study, patients were returned to their

original LT4 dose.

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Laboratory Testing

For safety purposes, and to ensure that appropriate adjustments could be made in the LT3 dose,

all samples were assayed on the day they were drawn. The reference ranges for the thyroid

assays were as follows: TSH, 0.4 to 4.5 mIU/L (immunometric assay); FT4, 0.8 to 1.8 ng/dL;

total T4, 4.7 to 13.3 mcg/dL; FT3, 2.18 to 3.98 pg/mL; and total T3, 76 to 181 ng/dL (all

immunoassays).

Statistical Analysis

Changes in parameters (vital signs, metabolic parameters, thyroid function tests, biochemical

markers, and questionnaire data) from baseline to subsequent weeks were assessed using

repeated measures Analysis of Variance (ANOVA). A similar analysis was performed to

compare all weeks to week 2 (when T3 values were lowest and TSH values were highest). Some

parameters were log transformed to reduce skewness. Analysis was performed using separate

dose categories (15, 30, 45, and 60 mcg) to assess dose-ranging results. A mixed linear model

with time-varying covariates was also used to assess the association of T3 and FT3

concentrations with TSH concentrations, FT4 concentrations, T4 concentrations, vital signs,

metabolic parameters, biochemical markers, and questionnaire data. Two-tailed P values <.05

were considered statistically significant. A Bonferroni correction was used to adjust for

multiplicity.

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The maximum observed concentration (Cmax) and the time at which this occurred (Tmax) were

obtained from graphic representation of the data. The area under the curve (AUC) from 0.5 hours

to 8 hours was calculated using the trapezoidal rule and using the actual times of measurements.

Baseline correction was performed using the concentration at 0 hours.

Means with standard deviations (SDs) or medians with interquartile ranges for every time point

and variable were calculated for comparisons based on patient sex and race, and the Wilcoxon

rank sum test was used to identify any differences. Pearson and Spearman correlation

coefficients were calculated to identify correlations between physiologic parameters (height,

weight, body mass index, and age) and Cmax, Tmax, and AUC Correlations between parameters

were tested using a mixed-effects model, and adjustments were made for age, sex, and time.

All data were analyzed with SAS version 9.3 (SAS institute, Cary, NC).

RESULTS

Baseline patient demographics are summarized in Table 1.

The changes in Free T3 (FT3) and TT4 over the successive weeks of the study are shown in

Table 2a and Table 2b. TT3 levels showed a small decrease from 99.5 ± 22.9 ng/dL at baseline

to 91.9 ± 40.2 ng/dL at week 2 and recovered to 96.1 ± 32.2 ng/dL at week 6, a result of

increased LT3 dose. These differences were not significant (Figure 1a). However, FT3

concentrations showed a decline from baseline week 2 in the face of stable levels of T3 (Figure

1b compared to 1a) and was LT3 dose dependent (Figure 2b). Mean serum TSH levels increased

from 1.56 ± 0.81 mIU/L at baseline to 5.90 ± 5.74 mIU/L at week 2 (P = .0002). TSH values

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trended toward normalization at week 4 as T3 dosing increased and remained in the normal

range (Figure 1c) except for the thyroidectomized patient on 60 mcg T3 (Table 3). Total serum

T4 decreased over the course of the study and was LT3 dose dependent (Figure 2a). FT4

concentration reached a nadir of 0.45 ng/dL by week 5 and significantly decreased (P <.0001) to

a stable range of 0.44 to 0.45 ng/dL apparently from residual T4 production by the gland (Figure

1d).

After 6 weeks of TriThroid® treatment, a final pharmacokinetic (PK) evaluation was conducted

by taking hourly measurements following the final dose. In this final PK portion of the study, the

peak T3 concentration after TriThroid® administration was 292.8 ± 152.3 ng/dL, increased from

a baseline value of 96.1 ± 7.6 ng/dL (Figure 3a). Similar patterns were seen for the trough and

peak FT3 concentrations, with a trough of 2.67 ± 0.15 pg/mL and a peak of 6.51 ± 2.48 pg/mL

(Figure 3b). The Tmax values were 2.4 ± 1.5 hours and 2.22 ± 1.26 hours for T3 and FT3,

respectively. The mean AUC 0-8 hours was 655.6 ± 404.6 ng.h/dL for T3 and 12.4 ± 7.2 pg.h/dL

for FT3. There were no differences in AUC, Cmax, or Tmax values when patient age and sex

were considered. With the higher LT3 doses (45 and 60 mcg), the distribution half-life of T3

from the blood into the peripheral target tissue (extravascular) compartment increased, from 5.0

hours in Phase 1 pharmacokinetic studies 11 to 8.1 hours in this study, reflecting the increase in

available thyroid hormone binding in the blood, concomitant with depletion of serum T4 (Table

3). As expected, serum TSH and residual FT4 levels remained low and stable (Fig. 1c, 1d) and

did not change after administration of the final LT3 dose (Figures 3c and 3d).

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Vital signs (heart rate, temperature, systolic blood pressure, diastolic blood pressure, respiratory

rate) did not change during the study. The lowest values for weight and body mass index were

recorded at weeks 5 and 6. Lipid profile and ferritin did not change with the conversion to T3

therapy. SHBG decreased significantly at week 2 when participants were taking LT3 15 mcg (P

= 0.002) but was unchanged at weeks 0 to 1 compared with weeks 3 to 6 (Figure 4a).

The number of euthyroid symptoms reported was increased by weeks 4 and 5 (P =0.005 and .03,

respectively; Figure 4b). SF-36 Physical Component Scores were also significantly increased by

weeks 4 and 5 (P = 0.04 and 0.03, respectively; Figure 4c). Respiratory quotient, resting energy

expenditure, and SF-36 Mental Component Scores did not change during the study. However,

there was a significant correlation between improved euthyroid symptoms and serum T3 levels

(P = 0.04).

For the 6 weeks that patients were taking TriThroid®, participant preference for LT3 therapy

increased, such that 39% of all participants preferred TriThroid®, during weeks 4 to 6 (Figure

4d), whereas the preference for LT4 decreased to 20%. These trends remained the same

regardless of whether the patients had FT4 concentrations that remained at or above 0.5 ng/dL by

study end (n = 6) or FT4 concentrations that decreased to less than 0.5 ng/dL (n = 12) (insert in

Figure 1d).

No adverse events or toxicities were observed in patients treated with TriThroid® therapy.

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DISCUSSION

This study used an open-label, single-arm, crossover design with an initial transition dose

followed by dose ranging in the LT3 crossover phase. In this "seamless" design, patients entered

the 6-week study taking LT4, crossed over to LT3 treatment, and then returned to their original

LT4 dose at the end of the trial. Crossover clinical trial designs are considered optimal for

chronic conditions such as hypothyroidism and for settings in which a direct comparison of

treatments is desired.9 With crossover trials, fewer patients are required to obtain significant

results,10 as each patient serves as their own matched control. Additionally, serial treatment

comparison allows for a direct test of dose titration and bioequivalence between treatments.

Crossover studies also allow for calculation of bioequivalent dosing when dose ranging is

included in the crossover phase.

The Patented drug delivery technology used in TriThroid® allows for a regulated rate of release

of LT3 from the product (Figure 5) into the digestive system and into the blood compartment.

This sustained release is accomplished by using noncovalent binding of LT3 to the porous

internal surfaces of excipient carriers. In this patented technology, excipients are carefully

matched to the active pharmaceutical ingredient based on surface affinity for the drug and

surface area/porosity of the excipient carrier. After ingestion, LT3 is released from the excipient

by dissolution from the excipient surfaces and slow diffusion from the excipient pores (Figure 5).

Increased shelf stability (>3 years) is also enhanced by the removal of water and oxygen from the

formulated tablets and “molecular scrubbing" by vacuum pressure recycling of the product with

inert gas. Transport of T3 from the blood into the extra-vascular space, including target tissues,

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provides sustained effects of LT3 from oral administration of TriThroid®.

Approximately 20% of patients with hypothyroidism have symptoms that are not managed

effectively by the LT4 monotherapy provided in commercially available products. This

resistance to LT4 therapy can be the result of impaired and variable transport from the gut into

the blood compartment but may also be due to the diminished enzymatic conversion of LT4 (a

pro-drug) to LT3, an activation step that is necessary for thyroid hormone action in target cells.

TriThroid® overcomes these limitations by providing LT3 in a novel delivery system that

effectively obviates individual variation in the hypothalamic/ pituitary/thyroid axis, and the T4 to

T3 conversion process. The results of the phase 2/phase 3 trial described here suggest that once-

daily LT3 formulated as TriThroid® can fully replace products containing LT4, providing

effective management of hypothyroidism. This use of a “daughter” product in place of a pro-

drug is not without precedent. For example, terfenadine, the first non-sedating antihistamine, had

to be withdrawn from the market because of serious side effects. However, terfenadine is a pro-

drug for the metabolic formation of the active molecule fexofenadine, which is safer than the

parent compound. In the same way, these clinical trials demonstrate that LT3 formulated as

TriThroid® has benefits over products containing LT4 as a monotherapy.

The therapeutic goal of replacement therapy for patients with hypothyroidism is to attain

sustained thyroid effects in target tissues, resulting in the maintenance of a euthyroid state. Once-

daily monotherapy with LT3 from TriThroid® meets this goal by providing sustained release of

LT3 and by enhancing LT3 binding to serum thyroid hormone-binding proteins through

reduction of serum T4. This increase in available serum thyroid hormone-binding sites extends

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the residence time of LT3 in the blood compartment, thereby enhancing the sustained effects of

dosing (Figure 3a). The results of this study support this model; as is shown in Table 3, LT3

doses of 45 and 60 mcg decreased T4 levels to less than 1/20 of the pre-dosing level and more

than 99.7% of T3 is bound to serum components at the end of the study, as calculated from FT3

and TT3 levels shown in Fig 3a and 3b. Thus, the calculated clearance half-life of T3 from the

serum compartment into the extra-vascular space in the single dose Phase 1 studies was 5 hours11

while the clearance half-life of T3 at the end of 6 weeks of TriThroid® therapy in these Phase

2/Phase 3 studies, was 8 hours, when serum T4 was lowest.

Serum T4 levels decline over the 6 week study with the well-known 1 week half-life. In addition,

hypothyroid patients with Hashimoto’s thyroiditis have residual thyroid function. Seventeen of

the patients in this clinical study had intact thyroid glands with residual and variable production

of T4, resulting in serum T4 levels of about 1/3 the serum T4 levels at the start of the study (9.5

mcg/dl). Thus, the serum TT4 in these patients declined to 3.6 mcg/dl, a level below the

euthyroid reference range (4.7-13.3 mcg/dl). Importantly, this residual production of T4 by the

gland was sufficient to keep TSH in the normal range. In addition, the residual T4 to T3

conversion can continue to contribute to serum T3 levels. Trithroid® dosing at 45 mcg and 60

mcg T3 levels sufficiently depletes the T4 levels to the point that there is very little T4

contribution from the gland and the starting dose at study entry has gone through 6 half -lives

(1/64). At 60 mcg dosing, TSH levels are very high (8.93 mIU/L), as expected, and only the T3

contributed by Trithroid® is left (59 mcg/dl). This level of T3 is not enough to down-regulate

TSH but is high enough to maintain a euthyroid state at the target cell level, as indicated by the

observed maintenance of the indicators of thyroid status at normal levels. As a Result of

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declining T4 levels (Fig 2a), serum binding sites become vacated allowing enhanced T3

occupancy. In fact, the FT3 levels decline (Fig 2b) on a dose dependent basis with the highest T3

dose (60mcg) resulting in the lowest TT4 and FT3 level (Figure 2b). Taken together, the data

indicates that blood levels of TSH may not be a reliable indicator of thyroid status in hypothyroid

patients managed on Trithroid.

The management of hypothyroidism with TriThroid® depends ultimately on T3-dependent

expression and regulation of gene products in target tissues. In this context, multiple

measurements were taken during the course of the clinical trials and compared to prestudy

values, when the patients were managed with LT4 monotherapy. TriThroid® was found to

maintain these measures (including TSH, total cholesterol, triglycerides, ferritin, SHBG, systolic

and diastolic blood pressure, heart rate, respiratory quotient, resting energy expenditure and body

temperature) at prestudy levels (phase 2/3 aggregate data), when the patients were managed on

T4 alone.

A single compartment model for T3 half-life in the blood following TriThroid® ingestion is not

complete15. Treatment with oral TriThroid® provides the digestive system with T3, followed by

delivery to the blood and then to the extravascular compartment. However, the extravascular

reservoir can recycle T3 back to the blood and digestive system to extend the effective half-life

of T3 in the blood. Phase 1 Clinical Studies were consistent with this multi-compartment model

since log-transformed Serum T3 levels following Cmax were non-linear11. Thus, a limited focus

on short-term blood levels of T3 may not be an accurate measure of thyroid hormone

pharmacokinetics following oral ingestion of TriThroid®.

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Other trial designs were also considered for this study, but they were discarded for multiple

reasons. For example, patients with newly diagnosed untreated hypothyroidism are very difficult

to recruit. Incorporating a placebo arm is considered unethical, and parallel treatment arms

would not contribute additional comparative data when compared with crossover trials. It would

also be very difficult to identify and recruit a subgroup of patients with hypothyroid symptoms

that are resistant to LT4 therapy, and this more patient-targeted clinical trial would be protracted

due to a paucity of participants. Identification and treatment of this group of patients may be best

suited to an after-market Phase 4 program in which prescribing healthcare professionals can

individually identify these patients as resistant to T4 monotherapy.

The current trial was designed to extend previous dose-ranging studies to determine optimal

dosing.11 Hypothyroid symptoms were effectively managed in patients treated with 45 and 60

mcg LT3. Based on these results, we believe that symptoms in most patients will be effectively

managed in adults with doses ranging from 45 to 90 mcg with 15 and 30 mcg used as transition

doses. As with other oral thyroid hormone replacement therapies, LT3 delivered from

TriThroid® requires individual dose titration to obtain optimal clinical end-points.

CONCLUSION

For many years, thyroxine-based products have been the main tool in our therapeutic toolbox for

the management of hypothyroidism and clinical experience has shown that symptoms in many

patients with hypothyroidism can be effectively managed with thyroxine-containing products.

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However, we now know that thyroxine is an inactive pro-drug that requires enzymatic

conversion to LT3 for physiologic activity and will be ineffective in patients who cannot

effectively convert LT4 to LT3.

This Clinical Trial demonstrated that TriThroid® can serve as a mono-therapeutic replacement

for thyroxine-based products in the management of hypothyroidism. Conversely, thyroxine-

based products do not effectively treat patients who do not adequately convert T4 to T3, are

allergic to thyroxine, or have defects in hormone transport from the gut into the blood, as with

celiac disease, or from the blood into target cells. In addition, critically ill patients with high

inflammatory loads may require TriThroid® therapy to offset elevated systemic thyroid hormone

degradation.17

Importantly, the current study reports that patients prefer TriThroid® replacement therapy over

LT4 formulations and the number of euthyroid symptoms increased by study week and the

number of hypothyroid symptoms decreased.. This Clinical study effectively adds TriThroid® to

our therapeutic toolbox for management of hypothyroidism and establishes that transition of

patients from levothyroxine to TriThroid® monotherapy may be accomplished with satisfactory

results.

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COMPETING INTERESTS

The authors declare that they have no competing interests.

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COMPLIANCE WITH ETHICAL STANDARDS

This Clinical Study was approved by the Institutional IRB at Georgetown University.

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ACKNOWLEDGMENTS AND FUNDING

The authors wish to thank LIAS Research, the Clinical Trials Office and Services at Georgetown

University, and Biomedical Communications at East Tennessee State University, and Ms. Megan

Griffiths for her editorial support of this manuscript.

These Clinical Trials are funded by ITL Pharma, Kingsport TN 37660. This manuscript is a

formalization of a limited data summary prepared by the Clinical Trials Office at Georgetown

University20.

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In, Clnical Endocrinology I (Astwood, E.B.,ed.) Grune & Stratton, Inc., New York, 1960,

103-111.

14. US Patent 9,526,701.

15. Goede S, Latham K, Leow M, Jonklaas J. High Resolution Free Triiodothyronine-

Thyrotropin (FT3-TSH) Responses To a Single Oral Dose of Liothyronine In Humans:

Evidence of Distinct Inter-Individual Differences Unraveled Using an Electrical Network

Model.In, Journal of Biological Systems, Vol 25, No.1 (2017) 1-25, World Scientific

Pub. Co.

16. ITL Pharma, Inc., Laboratory Measurements of Excipient Bound Water.

17. Salmaan K, et.al. Triiodothyronine replacement in critically ill adults with non-thyroidal

illness syndrome. Can J. Anesth/J Can Anesth (2018)65:1147-1153.

18. Levothyroxine Stability: www.accessdata.fda.gov/scripts/ires/index.cfm

19. Tseng Y, Latham K. Iodothyronines: Oxidative deiodination by hemoglobin and

inhibition of lipid oxidation. Lipids 1984, 19:96-102.

20. Jonklaas J, Burman KD. Daily Administration of Short-Acting Liothyronine Is Associated with

Significant Triiodothyronine Excursions and Fails to alter Thyroid-Responsive Parameters.

Thyroid 2016; Volume 26 Number 6 http:/DOI: 10.1089/thy.2015.0629.

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Table 1. Baseline patient characteristics and thyroid hormone doses

Sex/Age (y)

Weight

(kg)

Race

Etiology of

hypothyroidism

Entry LT4

dose (mcg)

Final LT3

dose (mcg)

F/25 81.9 Hispanic Hashimoto's thyroiditis 137 30

F/24 65 White Hashimoto's thyroiditis 88 30

F/35 55.5 Asian Hashimoto's thyroiditis 75 30

M/43 94.7 White Hashimoto's thyroiditis 75 30

F/24 68.3 White Hashimoto's thyroiditis 75 30


F/32 131.2 Black Hashimoto's thyroiditis 75 30




F/56 66.5 Black Hashimoto's thyroiditis 112 45







M/50 96.9 Black Thyroidectomy 150 60

2

Figure 1. Thyroid analyte concentrations by study week (mean ± standard error).

2

Table 2a. Serum T4 Levels 30,45 and 60 mcg over Study Period.

T4 30 mcg

Pt 0-Base Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6

AP5 Female 10.9 6.3 4.2 3.7 3.0 4.0 3.1

JT1 Male 8.7 8.6 8.4 7.5 7.2 7.9 7.2

DZ8 Female 7.9 5.3 4.4 4.4 3.3 4.1 3.5

AD2 Female 14.5 12.6 10.8 9.5 9.3 9.3 8.1

BC13 Female 12.4 12.3 9.9 10.4 9.5 11.3 11.1

MN19 Female 9.3 6.1 6.3 4.4 1.8 5.2 4.7

MD20 Female 7.5 6.8 5.7 5.6 4.9 4.9 3.4

KH21 Female 7.9 4.9 7.8 6.0 5.9 6.2 7.9

PH31 Female 7.1 4.0 1.9 3.6 2.9 3.3 4.9

Average 9.6 7.4 6.6 6.1 5.3 6.2 6.0

SD 2.521794 3.121698 2.889637 2.501389 2.851949 2.712062 2.733791

T4 45 mcg


KJ10 Female 7.9 5.3 1.8 3.9 2.2 1.8 1.1

GC11 Female 9.1 6.6 2.3 2.3 1.4 1.0 0.9

LL6 Female 11.3 5.7 3.6 4.1 2.5 2.5 1.1

SB18 Female 10.3 5.2 2.8 3.3 1.7 2.5

BS22 Female 9.0 6.2 5.7 2.4 3.2 3.0 1.3

LS26 Female 8.4 3.4 1.1 0.2 0.5 0.5 1.3

RF27 Female 8.5 6.8 5.1 2.6 2.6 1.5 1.7

Average 9.2 5.6 3.2 2.6 2.2 1.7 1.4

SD 1.189438 1.147461 1.70098 1.39523 0.998093 0.847405 0.539841

T4 60 mcg


WW25 Female 11.0 6.5 2.6 0.5 1.3 1.0 0.5

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Table 2b. Serum FT3 Levels 30,45 and 60 mcg over Study Period.

0 Base Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6

KJ10 Female 3.02 2.69 2.65 2.55 2.73 2.53 2.33

GC11 Female 2.67 2.49 2.09 2.08 2.49 2.29 2.36

LL6 Female 2.87 2.50 2.23 2.39 3.01 2.58 2.50

SB18 Female 2.54 2.44 2.02 2.00 1.97 2.02

BS22 Female 2.77 3.41 3.68 3.05 2.80 2.92 3.84

KJW24 Female 2.69 2.65 1.95 3.03 2.10 1.98 2.40

LS26 Female 2.55 2.23 1.65 2.52 2.16 2.62 3.00

RF27 Female 2.57 1.63 2.11 2.75 1.73 2.02 1.62

Average 2.25 2.15 2.04 2.32 2.20 2.24 2.41

SD 0.99 0.87 0.80 0.77 0.72 0.73 0.94

FT3 45 mcg

Pt


WW25 Female 2.61 1.74 1.31 1.95 2.34 1.69 1.70

FT3 60 mcg

Pt

FT3 30 mcg

Pt 0 Base Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 Wk 6

JT1 Male 3.14 2.86 3.42 2.92 3.45 3.53 3.52

DZ8 Female 3.06 2.92 2.93 3.04 2.74 2.72 2.88

AD2 Female 3.13 3.50 3.07 3.23 3.46 3.28 3.32

BC13 Female 3.28 3.52 3.14 3.45 3.41 3.07 3.46

MN19 Female 2.87 2.44 2.03 2.12 2.07 2.04 2.28

MD20 Female 2.94 3.20 2.96 3.05 2.75 3.10 3.29

KH21 Female 3.33 3.63 3.62 2.84 2.95 2.98 2.98

PH31 Female 2.44 2.44 2.30 2.09 2.46 3.18 2.30

Average 3.02 3.06 2.93 2.84 2.91 2.99 3.00

SD 0.28 0.47 0.53 0.49 0.51 0.45 0.49

2

Figure 2. Total Serum T4 and Free T3 by Dose and Study Week.

0.0

2.0

4.0

6.0

8.0

10.0

12.0

0-Base Wk 1-15 Wk 2-15 Wk 3-30 Wk 4-30 Wk 5-30 Wk 6-30

Tota

l Ser

um

T4

(m

cg/d

l)

Study Week

Figure 2a. Total Serum T4-30,45,60 mcg Dose

Serum T4-30mcg Dose Serum T4-45 mcg Serum T4-60 mcg Dose

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50


Seru

m F

ree

T3 (

pg/

ml)

Study Week

Figure 2b. FT3-30, 45, 60 mcg Dose

FT3- 30 mcg Dose FT3-45 mcg Dose FT3 -60 mcg Dose

2

Table 3. Effect of LT3 Dosing on Serum T3, T4, and TSH Levels at Study End

( 6 wks)

No.of

Patients

LT3 dose

(mcg)

Time on

Dose

Serum T3

(ng/dl)

Serum T4

(mcg/dL)

Serum TSH

(mIU/L)

18 Baseline 0 99.5 +- 22.9 9.5 ± 1.9 1.56 +- 0.81

18 15 2 weeks 91.9 _ 40.2 4.9 ± 2.8 5.90 +- 5.74

8 30 4 weeks 107.2 +_ 32.5 6.0 ± 2.6 2.13 +-1.14

8 45 4 weeks 86.4 +_ 15.6 1.3 ± 0.5 3.0 +-3.84

1 60 4 weeks 59.6 0.5 8.93

2

Figure 3. Thyroid analytes during the final pharmacokinetic portion of the study (mean ±

standard error).

2

Figure 4. (a-d) Changes in markers of thyroid status over the course of the study (mean ±

standard error).

2

4d. TriThroid® Preference by Study Week

2

Figure 5. Dissolution Profile

In vitro dissolution studies demonstrated the sustained-release effects as described in the coating

technology patent14 Phase O and Phase 1 clinical studies demonstrated a longer Tmax with LT3

100-mcg and 50-mcg dosage of TriThroid® (BCT303) when compared with Coastal, Cytomel,

and Mylan LT3 generic products.

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