A clinical trial comparing Armour Thyroid (NDT) and Levothyroxine (LT4) is now recruiting patients in the United States.

The sponsor of the study is Allergan, the makers of Armour Thyroid in the United States. They hope to recruit 220 patients at multiple locations listed on the clinical trial website.

In this post, I provide what is known of the study details, and then engage in thyroid science commentary, raising our hopes for the useful, objective scientific insights this trial might reveal.

Outline

• Study details
  • Inclusion criteria
  • Exclusion criteria
• Commentary
  • Is an Allergan-sponsored study going to be biased?
  • Not a superiority trial, thank goodness.
  • The T3-Dominant ratio in desiccated thyroid
  • But how will you assess dose conversion?
  • Please, TSH is not the ruling judge of safety or efficacy.
  • Will the study acknowledge diverse patient response?
  • Will they multi-dose?
  • High hopes and best wishes
• References

Study details

The official name of the study is a mouthful:

A Multicenter, Randomized, Double-blind, Dose-conversion Study to Evaluate the Safety and Efficacy of Hormone Replacement Therapy With Armour® Thyroid Compared to Synthetic T4 (Levothyroxine) in Previously Hypothyroid Participants Who Are Euthyroid on T4 Replacement Therapy

https://clinicaltrials.gov/ct2/show/NCT04124705

• The Allergan website explains “This study will evaluate the safe and effective dose conversion from synthetic T4 therapy to Armour Thyroid therapy in participants who are euthyroid on a stable dose of synthetic T4.”
• They say ” Oral administration once daily,” which could mean that they will administer doses 1x a day.
• Their primary and secondary outcome measures focus on TSH only.

Inclusion criteria

• Participants who have a diagnosis of primary hypothyroidism made ≥ 12 months before study entry (Visit 1).
• Be on continuous thyroid replacement therapy with synthetic T4 for primary hypothyroidism for at least 12 months immediately prior to the Screening Visit (Visit 1).
• Be on a stable FDA-approved daily dose of synthetic T4 for a minimum of 3 months prior to the Screening Visit (Visit 1). Must enter the study on the same stable dose.
• Have euthyroid status indicated by at least 1 documented TSH value within normal reference range (0.45 4.12 mIU/L, inclusive) at a minimum of 6 weeks and maximum of 12 months prior to the Screening Visit (Visit 1). Also have a confirmed TSH value within the normal reference range drawn at the Screening Visit (Visit 1).
• Male and female participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study and follow-up period (35 days after last dose of study intervention).

Exclusion criteria

• Any clinical condition or previous surgery that might affect the absorption, distribution, biotransformation, or excretion of Armour Thyroid or synthetic T4.
• History of alcohol or other substance abuse within the previous 5 years.
• Known or suspected allergy or intolerance to any ingredients of Armour Thyroid, including its excipients, levothyroxine (T4), other thyroid replacement medications, or pork products.
• Have received active treatment with an investigational drug within 30 days or 5 half lives, whichever is longer, of Screening Visit (Visit 1).
• Current enrollment in an investigational drug or device study or participation in such a study within 60 days of entry into this study.

Commentary

Since the 1980s, a study of desiccated thyroid has been a very rare event.

The rise of modern clinical trial methodology happened after the era in which most studies of desiccated thyroid therapy were published.

The ONLY “randomized, double-blind” clinical trial comparing LT4 and desiccated thyroid was published in 2013 by Hoang et al. Hoang’s study also titrated doses to the TSH. They found that neither Levothyroxine nor desiccated thyroid were superior to each other. Unfortunately for patients, their abstract hinted that their preference for desiccated thyroid could have been due to feeling happy about some weight loss, a remark that makes light of this benefit and underemphasizes the finding of the equal safety and effectiveness of the pharmaceuticals.

More recently, Tariq et al (2019) did a retrospective study (not a double-blind controlled trial) of desiccated thyroid compared to synthetic T3-T4 combination over an average of 27 months (1 month to 9 years). This study found many clinical benefits of both “natural” and “synthetic” combination therapy at different ratios, while dosing to normalize TSH, FT3, and FT4 at all times. There were NO “risks of atrial fibrillation, cardiovascular disease, or mortality in patients of all ages with hypothyroidism.”

Is an Allergan-sponsored study going to be biased?

Having a drug study sponsored by the drug company that makes it is fairly common in clinical trial practice.

It involves some potential conflict of interest in the study design and the publication of data.

Savovic et al, 2018 has written a concise overview of the issues, saying this:

“Conflicts of interest do not necessarily cause biased trial results, but create the risk thereof.”

The challenge with studies of desiccated thyroid trials has been the opposite sort of bias and conflict of interest: LACK of study.

Proponents of Levothyroxine have refused to engage in clinical trials on desiccated thyroid for decades.

Then they say in guidelines that it’s not recommended because not enough research exists. They thereby openly and shamelessly admit thyroid endocrinologists’ refusal to study it. They make sweeping prohibitions based only on opinion and ignorance — this is anti-scientific pharmaceutical prejudice at its worst.

Imagine if a bunch of rich males decided that they wouldn’t do any medical research on females’ medication needs, basically making things really bad for women who respond differently to medications. What’s wrong with a few rich females funding a study that finally includes females and some meds that might work better for some of them? Oh no, (the biased men will say), they’re biased, and we’re not.

Sex prejudice is taboo, but thyroid pharma prejudice is not yet taboo.

Extremist attitudes are easy to find in segments of the endocrinology community. An infamous anti-desiccated thyroid trial in brazenly declared its bias in its title, “Why does anyone still use desiccated thyroid USP?” (Jackson & Cobb, 1978). Can you hear the sneer? This is the kind of pharmaceutical arrogance and defamation that is permissible among pharma-bigoted physicians, even today, as we hear reports that some doctors are unashamed to voice their vitriolic hatred for this medication to patients who request it.

If desiccated thyroid is so unsafe and ineffective, why was it the gold standard of thyroid therapy long after the mass marketing of levothyroxine began in 1949? Opinions did not shift toward sysnthetic LT4 until the 1970s, and the shift toward levothyroxine was not based on any rigorous clinical trial showing the “superiority” of levothyroxine in terms of long term clinical outcomes. Instead, it was based on medical convenience plus the distaste for T3-dominant biochemistry at a time when people feared isolated transient FT3 elevations without considering the counterweight of a relatively lower FT4.

Therefore, having a trial sponsored by Allergan is far less likely to be discriminatory against desiccated thyroid than if the study was sponsored by the makers or champions of the competing pharmaceutical, synthetic Levothyroxine.

In addition, having a study sponsored by them is better than continuing for another decade only having one double-blind clinical trial attesting the safety and equal efficacy of both LT4 and desiccated thyroid (Hoang et al, 2013).

Not a superiority trial, thank goodness.

Thyroid patients are sick and tired of the litany of synthetic T3-T4 combination trials that have been so poorly designed and which often portrayed as “failure” something quite innocent–the inability to achieve superiority.

Why does one thyroid drug have to be intrinsically superior to another? These are bioidentical hormones, not chemicals foreign to the body.

We all secrete and convert T4 and T3, and one bioidentical hormone is not intrinsically more dangerous than the other when dosed properly.

ALL thyroid medications are capable of being dosed safely and effectively according to an individual’s needs. But NOT ALL patients will respond well to all thyroid pharmaceuticals.

Thyroid pharmaceutical prejudice inevitably results in narrowing the pharmaceutical marketplace, which creates monopolies and harms patients. It is a form of prejudice against patients who only respond well to a less favored thyroid medication or a highly customized ratio of T3 and T4.

Thyroid pharma prejudice can also be anti-synthetic. One should admit that the synthetic thyroid hormone drugs have been carefully engineered to be structurally identical to our own. Enough biochemical study has proven that the human body binds, transports, and converts externally-sourced T3 and T4 molecules in blood the same way as it does internally-sourced thyroid hormone molecules. We even know that the rotation of the molecule’s outer ring is important, and that’s why it’s called Levo-thyroxine not Dextro-thyroxine, which signifies the direction of the rotation. Early studies with synthetics found that the body responds to dextrothyroxine very differently and not as well overall.

So Allergan, thank you, thank you for merely focusing on determining “safe and effective dose conversion” and not making this into a horse race competition.

The T3-Dominant ratio in desiccated thyroid

Here’s another reason why we really need this study.

Far too much anxiety has been spent on worrying that desiccated thyroid does not mimic the “average” healthy thyroid gland secretion ratio of T3 and T4, an average that is found within a wide range of secretion ratios.

Even scientific minds can be duped into thinking that dosing “extra” T3 will lead to “excess” T3, forgetting that dosing only T4 doesn’t necessarily lead to excess T4. Our individualized thyroid hormone metabolism transforms what we dose.

Too many studies have limited “experimental” T3-based thyroid dosing to T3:T4 ratios of 1:14 or 1:16 T3 to T4 micrograms. This is the ratio that is widely yet falsely claimed to be “physiologically correct.” It is not. It is an unnaturally rigid and narrow ratio based on misinterpretation of Pilo’s 1990 kinetic study.

The thyroid gland is a flexible secretor of variable ratios of these two hormones, and the average secretion ratio of T3 and T4 varies widely between individuals, and even daily, within healthy-thyroid individuals (but we lose our daily FT3 fluctuation in LT4 monotherapy).

Even dietary or supplementary iodine supply can shift the T3:T4 secretion ratio.

Besides, FT3:FT4 ratios in blood are far more physiologically significant than ratios in secretion or dosing. A gland’s secretion ratio need NOT be the same as a dosing ratio because the pharmaceutical delivery method is extremely different from natural production.

• Note: In bloodstream, T4 is usually lower in its range than the fluctuating daily average T3 levels in desiccated thyroid therapy. It was not widely understood in the 1970 and 80s, when the most harsh attacks on desiccated thyroid occurred, that more FT3 in blood is metabolically required to compensate for lower FT4. This T3-dominant ratio in bloodstream is not unnatural. It mimics the natural adaptation that occurs in asymptomatic subclinical hypothyroidism when T4 loss triggers a major increase in T3 synthesis and T4-T3 conversion, preventing T3 from falling low prior to therapy. This benignly T3-dominant T3:T4 ratio in blood is something we now understand better thanks to T3 monotherapy studies such as Celi et al in 2010-2011 and Busnardo et al in the 1980s, which examine how higher levels of T3 are necessary to maintain physiological functions in the complete absence of FT4 from bloodstream. Desiccated thyroid therapy results in varying FT3:FT4 ratios depending on the patient.

LT4 monotherapy is certainly not a physiologically correct ratio, because it is devoid of T3, and yet it is safely dosed for many people who convert T4 hormone well enough to achieve their personally euthyroid FT3 and FT4 levels during therapy.

Desiccated thyroid is especially helpful for patients who do not convert T4 hormone efficiently. The medication enables such patients to access Free T3 higher-normal levels and a T3-dominant profile that does not yield thyrotoxicosis. This would not be possible for them on LT4 monotherapy.

Let’s adjust the dosing ratio to the individual, rather than forcing all individuals to adapt to one “magic molar ratio.”

All thyroid therapy is artificial, and what is “abnormal” for people with thyroids can nevertheless be therapeutic for the individual with a disabled, dead or missing thyroid gland.

Hopefully this desiccated thyroid trial will help the thyroid community get over the silly T3-T4 dosing ratio obsessions by showing, once again (after Hoang’s and Tariq’s recent studies), that a 1:4.2 ratio can be as effective as a 1:14 and a 0:100 ratio, depending on the patient’s thyroid disabilities and how you dose it.

But how will you assess dose conversion?

Allergan wishes to examine “the safe and effective dose conversion from synthetic T4 therapy to Armour Thyroid therapy.”

The Armour Thyroid product information pamphlet says “T3 liothyronine is approximately four times as potent as T4 levothyroxine on a microgram for microgram basis”

However, a 4 mcg LT4 to 1 mcg LT3 dosing conversion ratio is highly questionable!

Allergan understands how crucial this is for thyroid therapy. If the dose conversion estimate is way off, many people will be underdosed by replacing too much LT4 with too little desiccated thyroid.

One must do the math and consider that 9 mcg of T3 and 38 mcg of T4 is in 60g of Armour desiccated thyroid when substituting Armour for Synthroid, and realize that the estimate is just a starting point to see what the body will do as it transforms the dose to FT4 and FT3 levels. The math does not have to be perfect, just not way off.

It’s likely that Allergan has been paying attention to trends in thyroid therapy (and likely the frequent occasion of underdose of Armour Thyroid by T3-fearful doctors). They likely had plans in the works for an equivalency / conversion study long ago.

This “pharmaceutical equivalency” per microgram of LT3 and LT4 (and desiccated thyroid) was the topic of two articles that we at Thyroid Patients Canada posted in September, 2019:

• “No, 25 mcg of L-T3 Liothyronine isn’t equivalent to 100 mcg L-T4“
• “L-T3 pharmaceutical equivalency, Part 2: New thyroid science“

In my past articles, I have provided an in-depth historical and scientific critique such claims, showing that the equivalency is closer to 3x rather than 4x, and also that the dosing equivalency ratio of LT4 mcg to LT3 mcg is very individualized.

According to one clinical trial on LT3 vs. LT4 monotherapy, the same target TSH value was achieved at a ratio closer to 3 times the potency, but it varied among individuals (Celi et al, 2010, 2010; Yavuz et al, 2013).

Please, TSH is not the ruling judge of safety or efficacy

Given the contemporary context of TSH-worship, I’m worried by the fact that their primary and secondary outcome measures seem to focus on TSH only.

On their website, not enough detail was provided regarding their proposed methods.

When considering “safe and effective dose conversion,” hopefully the study will measure more than just the TSH response of the patients between LT4 and DTE (desiccated thyroid extract), just as the publications by Celi and Yavuz did that determined a dose equivalency for LT3 and LT4 monotherapies.

Please, Allergan, learn from Celi and Yavuz’s studies.

Celi and Yavuz targeted a TSH from 0.5–1.5 mU/L for their comparison of the two pharmaceuticals, knowing that the vast majority of healthy people have a TSH below 2.5 mU/L and that the TSH population range is way too wide for any healthy-thyroid individual.

They also carefully regulated the patients’ diet during the trial, knowing that calorie restriction lowers TSH by altering leptin signaling in the hypothalamus.

They also measured multiple biomarkers of thyroid hormone action beyond the hypothalamus and pituitary, such as serum glucose, cardiovascular function, body composition, quality of life, exercise test, and other factors.

Yavuz et al, 2013 is the third article that came out of a very rich, detailed study of LT4 and LT3 pharmacokinetics. In that final article, they returned to their idea of targeting a low-normal TSH. They seriously questioned whether the patients were truly “euthyroid” on either medication even when their TSH was lower in reference!

They justly called TSH normalization “Pituitary Euthyroidism” because it a form of euthyroidism that exists at the pituitary alone.

“This modality of treatment [TSH-normalized LT4 monotherapy] is based on the assumption that a state of pituitary euthyroidism (ie, a TSH level within normal range) equates to a state of euthyroidism in all target tissues.”

But Yavuz and colleagues found that this widespread assumption was highly suspect.

When you achieve normal TSH by different ratios of T4 and T3 hormone dosing, you get some very different responses from “target tissues” beyond the hypothalamus and pituitary gland, especially improvement in cholesterol levels and body weight when FT3 is optimized.

“In this context, the data suggest that pituitary euthyroidism, both assessed by basal or TRH-stimulated TSH, does not necessarily equate to a state of generalized euthyroidism at the level of the different targets of the hormonal action. ”

Yavuz and team recommended T3-T4 combination therapy trials and said

“more research must be done to characterize the optimal dosage and the population who may benefit from such intervention.”

Will this study by Allergan do anything to identify not just “optimal dose” but also the optimal “population” for intervention by means of more detailed measurement than just TSH?

Continue to Page 2

• Will the study acknowledge diverse patient response?
• Will they multi-dose?

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Will the study acknowledge diverse patient response?

When considering a “conversion” of dose from LT4 to desiccated, hopefully the study will consider differences between patients’ causes of hypothyroidism, their thyroid gland status, and their antibody status, and unique TSH – T3 setpoints.

• Midgley et al, 2015 has usefully illustrated the significant variation in response to LT4 monotherapy even among thyroidless patients. There are good converters of thyroid hormone, moderate converters, and poor converters.
• The “dose conversion” of LT4 to desiccated thyroid for a “poor converter” is likely going to be very different from that of a “good converter” even at the exact same TSH. The study may discover they may need higher doses to achieve equal TSH.

• Graves, Atrophic Thyroiditis and Hashimoto’s thyroiditis patients can have antibodies that directly interfere with TSH regulation by the pituitary gland at the ultrashort feedback loop. The TSHR stimulating antibody can be active even post-thyroidectomy, artificially lowering TSH despite lower FT4, and those with TSHR blocking antibodies tend to have exaggerated and fluctuating TSH levels (I’m one of those patients, so I know). This is why people with TSHR antibodies can achieve remission or flip-flop between hypothyroid and hypER status over 10 years until some people’s glands shrivel up (Takasu et al, 2012). It is rare for studies to measure TSH-Receptor antibodies in hypothyroid patients, but yeah, we have them, too.
• It is not impossible for a patient to have undiagnosed mild central hypothyroidism (impaired TSH secretion) in addition to primary hypothyroidism. When TSH secretion is abnormally lower, even by a small fraction, it can lead to underdose when doses are religiously adjusted to stay within the normal reference range. In addition, euthyroid T3 hormone dosing (even at higher doses of desiccated thyroid) can have a localized TSH-suppressive effect at the hypothalamus, an effect that shows up with TRH-TSH testing (Koutras et al, 1981).
• New research is showing that even on LT4 monotherapy, a TSH mildly below reference and a FT3 higher than midpoint of reference is where true euthyroidism exists for some types of patients (Ito et al, 2012, 2017, 2019; Larisch et al, 2018; Hoermann et al, 2019). This is the finding for a population of atrophic thyroid patients after Graves’ radioiodine therapy or athyreotic patients post-thyroidectomy, but even Hashimoto’s patients can have utterly fibrosed and inactive thyroid tissue. Those with little to no thyroid gland tissue have the statistically largest TSH-T3 disjoint, since they cannot benefit from thyroid tissue’s ability to enhance conversion of T4 to T3 via the “TSH-T3 shunt”…
  
  What is the “TSH-T3 shunt”? (see Berberich et al, 2018.) Briefly, it’s the way that a thyroid gland acts as a TSH-regulated T3 optimizer. But in thyroid disease, we each have different amounts of functional thyroid tissue that can still convert hormones, and this changes our T4-T3 conversion rate as blood flows through the thyroid gland with various concentrations of TSH (or TSH receptor antibodies that mimic TSH). Thyroid tissue expresses both Deiodinase Type 1 and 2. You cannot judge by dosage alone how much remnant thyroid tissue a person has or how fibrosed or atrophied (dead) the thyroid gland has become. Such can be estimated by ultrasound with measurements of a thyroid’s dimensions and obtaining data on its echogenicity.

• It would have been wiser to limit recruitment to patients with total thyroidectomies so that this “wild card” of active thyroid gland secretion of T4 and T3 — this significant variable of unknown potency — can be controlled.

Please try to divide us into cohorts by thyroid disease type and gland health.

Please express results as a range and publish a study that gives a vivid scatterplot graph showing where individual data points are.

A static “equivalency” of LT4 dosing to Armour Thyroid dosing is very unfair and unrealistic to the individual thyroid patient. An “average” when all thyroid patients, regardless of dose or conversion rate, are lumped together, is not representative of the unique metabolic challenges faced by each cohort.

Will they multi-dose?

Another challenge with this study regards multi-dosing several times a day.

This is a major controversy in T3-T4 combination clinical trials, with some people blaming the combination’s failure to achieve “superiority” over levothyroxine on the fact they were not dosing the T3 medication two or three times a day to even out patients’ Free T3 levels.

Dosing 1x a day not wise if the dose is larger than 120 mg/day (two grains), given that the content of 60 mg Armour is 9 mcg T3 and 38 mcg T4 according to the product information pdf, and there is a considerable short-term peak and valley in Free T3 after dosing T3.

If they do measure T3 concentrations, they will need to measure them outside of the volatile peak hours when waiting 20 minutes can yield a significantly different result.

The larger the NDT dose, the higher the FT3 peak will be, but it won’t last much longer over time.

If you dose in the morning, you could be hypothyroid by evening … if you’re riding on FT3 to sustain you because you can’t convert enough T4 locally in cells.

During a higher Peak FT3, some may have mildly higher heart rates and other fast acting metabolic responses.

When the peak FT3 is very high, it is likely that Deiodinase Type 3 will be triggered in tissues. D3 enzyme will increase the rate of T3 conversion to T2 and the rate of T4 conversion to Reverse T3, which means less hormone is converted to the active form T3 in cells.

The loss of T3 from cells due to local hormone inactivation in tissues is not as likely to be noticed in blood when you are resupplying T3 daily, but it can make a difference to various organs and tissues at the local level.

Symptoms may be confusingly both hypo and hyper if T3 and T4 levels are, either separately or combined, higher than the metabolic setpoint for an individual patient, the state that upregulates Deiodinase type 3. The three deiodinases can be imbalanced in a different ways in each tissue and organ, and T3 and T4 exchange with tissues at different rates over time, meaning some symptoms of local T3 loss show up earlier, some later.

How much is too much? Given that the healthy range for Free T3 is as narrow as 38% of reference range, you cannot predict where a person’s upper or lower boundary of their FT3 setpoint lies in relationship to statistical population reference ranges. There is no absolute FT3 target that fits everyone, just a general rule of thumb that the lower half of reference is where thyroid patients tend to suffer hypothyroidism. One has to safely creep up toward optimal levels in dose adjustments, not mistaking pituitary euthyroidism (statistically normal TSH) for generalized euthyroidism, as Yavuz and team wisely caution.

Science already knows what can happen when higher T3 thyroid hormone levels are insufficient for some organs but excessive for others. A contradictory symptomatic presentation has long been recognized in the syndrome called Resistance to Thyroid Hormone (RTH), in which “thyroid hormone deficiency and excess coexist” while the body requires abnormally higher thyroid hormone levels (Dumitrescu & Refetoff, 2013).

• In a nutshell, RTH patients have a genetic insensitivity in one thyroid hormone receptor family, THRB, but not the other, THRA. Some tissues express primarily THRB, others THRA. They need more circulating T4 and/or T3 to activate their THRB receptors in brain while their THRA receptors in heart are overactivated. If the THRB receptors in the pituitary are affected, the TSH will not be suppressed by higher levels of thyroid hormone, but some genetic variants are pituitary specific and affect the TSH secretion, others generalized and affect multiple organs. The presentation varies from patient to patient and can be mild or severe.

Given that excessive transient Free T3 peaks can trigger deiodinase imbalances and weirdly contradictory symptoms like those seen in RTH, multi-dosing is a way to ensure adverse responses don’t occur during desiccated thyroid therapy trials.

High hopes and best wishes

Thyroid patients who have experience with desiccated thyroid therapy are eager to know what you discover through this clinical trial.

Not all clinical trials are successfully completed, either due to lack of participants or funding, or other unexpected challenges.

Not all results of trials are published. Sometimes the process of publication can be delayed during data analysis, scientific peer review, or editing processes.

We hope our article helps to recruit enough participants. Please do not hide or delay your findings. Publish them as soon as you can.

• Tania S. Smith on behalf of Thyroid Patients Canada

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References

Allergan. (2019, October 11). A Study of Armour® Thyroid Compared to Synthetic T4 (Levothyroxine) in Previously Hypothyroid Participants—Full Text View—ClinicalTrials.gov. Retrieved December 30, 2019, from https://clinicaltrials.gov/ct2/show/NCT04124705

Allergan. (2018, June). Armour® Thyroid (thyroid tablets, USP) [Product prescribing information]. Retrieved from https://media.allergan.com/actavis/actavis/media/allergan-pdf-documents/product-prescribing/06-2018-Armour-Thyroid-PI-final.pdf

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