Phase 3 Randomized Double‑Masked Placebo‑Controlled Study of Subcutaneous Efgartigimod Alfa in Adults with Graves’ Disease Inadequately Controlled by Antithyroid Drugs

The primary objective is to demonstrate the efficacy of efgartigimod PH20 subcutaneous pre‑filled syringe compared with placebo in adult participants with Graves' disease who remain inadequately controlled on antithyroid drugs.

Secondary objectives include:

• Further demonstration of efficacy of efgartigimod PH20 SC PFS versus placebo in the same population.
• Characterization of the overall treatment effect of efgartigimod PH20 SC PFS compared with placebo.
• Evaluation of the effect of an additional 24‑week course of efgartigimod PH20 SC PFS versus placebo.
• Assessment of the ability of efgartigimod PH20 SC PFS to induce remission.
• Evaluation of safety and tolerability of efgartigimod PH20 SC PFS versus placebo, including long‑term safety.
• Assessment of impact on health‑related quality of life and patient‑reported outcome measures.
• Evaluation of the pharmacokinetic, pharmacodynamic and immunogenicity profile of efgartigimod PH20 SC PFS in this patient group.

The trial enrolled 85 adults (both male and female) aged 18 years and older who had a documented diagnosis of Graves' disease with anti‑thyrotropin receptor antibody levels at or above the upper limit of normal, active hyperthyroidism (TSH < 0.1 mIU/L), and a minimum of three months of treatment with methimazole or carbimazole prior to screening. Participants were selected on the basis of these clinical and laboratory criteria, reflecting an inadequately controlled disease state despite antithyroid drug therapy. No specific lifestyle restrictions or requirements, such as diet or physical activity, were reported for the study population.

The study is a Phase 3, multicenter, randomized, double‑masked, placebo‑controlled trial evaluating subcutaneous efgartigimod PH20 in adult participants with Graves’ disease whose hyperthyroidism remains inadequately controlled despite at least three months of methimazole or carbimazole therapy. Eligible subjects are randomized in a 1:1 ratio to receive either the active product (Vyvgart 1 000 mg solution for injection) or a matching placebo, with dosing administered subcutaneously according to the protocol schedule. The trial includes an initial screening visit to confirm diagnosis, TRAb ≥ ULN, TSH < 0.1 mIU/L, and minimum antithyroid drug exposure; a baseline/randomization visit; subsequent follow‑up visits at weeks 2, 4, 8, 12, 16, 20, and 24 to assess efficacy, safety, and laboratory parameters; and an end‑of‑study visit at week 24, followed by optional long‑term follow‑up assessments at 6, 12, and 18 months. Participant involvement therefore spans approximately 24 weeks for the primary evaluation period, with the possibility of extended observation for up to 18 months. Early termination may occur if a participant experiences a serious adverse event, withdraws consent, fails to meet compliance requirements, or if the investigator determines that continued participation is not in the participant’s best interest. The primary endpoint is the proportion of participants who achieve euthyroid status (fT3, fT4, and TSH within normal ranges) off antithyroid drugs at week 24, with secondary endpoints addressing time to euthyroidism, antibody levels, dose reductions, safety outcomes, and patient‑reported measures.

The investigational product is Vyvgart 1 000 mg solution for injection in a pre‑filled syringe, containing the active substance efgartigimod alfa. It is supplied as a sterile solution for injection and is administered by the subcutaneous route. Each dose consists of a 1 000 mg injection given once weekly throughout the treatment period.

The control arm receives a matching placebo designed to be indistinguishable from the efgartigimod PH20 SC pre‑filled syringe. The placebo is administered subcutaneously at the same volume, dose frequency, and schedule as the active product to maintain blinding.

Dosing is scheduled on a weekly basis, with each administration performed in the clinic under observation. Compliance is monitored by recording the date and time of each injection in the study case report form, and participants are required to complete a dosing diary confirming receipt of the study medication. Any missed or delayed doses are documented and reported according to protocol‑specified procedures. The study includes regular safety and efficacy assessments to evaluate outcomes in participants with Graves’ disease inadequately controlled by antithyroid drugs.

Efficacy will be primarily assessed by the proportion of participants who achieve euthyroid status, defined as free T3 (fT3), free T4 (fT4), and thyroid‑stimulating hormone (TSH) values within their respective reference ranges while off antithyroid drugs (ATDs) at week 24.

Secondary efficacy evaluations include time to achieve euthyroid status off ATDs, the proportion of participants who are euthyroid while receiving methimazole ≤5 mg/day or carbimazole ≤7.5 mg/day at week 24, the proportion with fT3 and fT4 below the upper limit of normal off ATDs at week 24, and the proportion who are euthyroid and thyroid‑stimulating hormone receptor antibody (TRAb) seronegative at week 24. Additional secondary measures comprise various time‑to‑event analyses (e.g., time to euthyroid, time to normal TSH, time to TRAb seronegativity), durability of euthyroid status without ATDs at multiple follow‑up intervals, changes in patient‑reported outcome instruments (ThyPRO‑39 and PROMIS‑PF10a), pharmacokinetic and immunogenicity parameters, and safety assessments.

Laboratory assessments of fT3, fT4, TSH, TRAb, total IgG, and efgartigimod serum concentrations will be performed using validated immunoassays at baseline and predefined visits, including the week 24 evaluation. Patient‑reported outcomes will be captured using the ThyPRO‑39 and PROMIS‑PF10a questionnaires administered at baseline and at scheduled follow‑up visits. Time‑to‑event endpoints will be derived from serial hormone and antibody measurements, with event dates recorded when predefined criteria are met. All data will be analyzed according to the study’s statistical analysis plan, employing appropriate categorical and survival analysis methods.