Evaluation of Safety and Tolerability of Teprotumumab Dosing Durations in Patients with Thyroid Eye Disease: A Phase 3b/4 Randomized, Double-Masked, Multicenter Trial
- Trial ID
- 2024-515090-96-00
- Protocol
- HZNP-TEP-402
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety**, tolerability, and necessity for re-treatment with three different durations of **teprotumumab** therapy in patients diagnosed with **Thyroid Eye Disease** (TED). This is clinically relevant as it aims to optimize treatment regimens, potentially improving patient outcomes and minimizing adverse effects associated with prolonged therapy.
Secondary objectives include:
- Change in proptosis measurement in the study eye
- Proptosis responder rate
- The overall responder rate
- Binocular diplopia responder rate
- Binocular diplopia resolution rate
- Change from baseline in Graves' Ophthalmopathy Quality of Life questionnaire appearance and visual functioning subscales
- Rate of flare at the end of the initial follow-up period
- Time to proptosis response during the initial treatment period
- Percentage of patients with a Clinical Activity Score (CAS) of 0 or 1 who had active disease (CAS ≥3) at baseline
- Percentage of patients who improve on CAS items: spontaneous orbital pain and gaze-evoked orbital pain
- Durability of complete response at the end of the initial follow-up period
- Durability of response at the last assessment in the initial follow-up period
- Percentage of patients with at least one treatment-emergent adverse event assessed as Grade 3 or higher
- Percentage of patients with at least one post-baseline abnormal laboratory result of Grade 3 or higher
- Effect of teprotumumab on the mean change from baseline over time in serum biomarkers for patients with a baseline CAS ≥3
Participants
The clinical trial investigating the safety, tolerability, and need for re-treatment of different **teprotumumab** treatment durations in patients with **Thyroid Eye Disease** includes a total of 81 participants. The study population comprises both male and female subjects, aged between 18 and 80 years. Participants were selected based on specific criteria, including an initial diagnosis of Thyroid Eye Disease within the past seven years and a requirement to be euthyroid or have mild hypo- or hyperthyroidism at screening. The trial includes individuals with controlled baseline disease and those who do not require immediate surgical ophthalmological intervention. Lifestyle considerations such as the use of reliable contraception methods are relevant for women of childbearing potential. The trial also accommodates diabetic patients with HbA1c levels ≤8.0% and individuals with a history of inflammatory bowel disease in clinical remission. The study population is characterized by a diverse age range and includes vulnerable populations, ensuring a comprehensive evaluation of the treatment's effects across different demographic groups.
Plans and Procedures
The clinical trial is designed to evaluate the **safety** and tolerability of different dosing durations of **teprotumumab** in patients with **Thyroid Eye Disease**. This is a Phase 3b/4, double-masked, randomized, international, parallel-assignment, multicenter trial. The trial will involve a placebo control, where the placebo consists of a normal saline (0.9% NaCl) solution administered in 100 mL or 250 mL infusion bags, based on weight-based dosing volumes. The trial is expected to run from June 2021 to August 2025, with the estimated duration of participant involvement being up to 140 days for the treatment period, followed by a follow-up period.
Participants will undergo a sequence of study visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of Thyroid Eye Disease within the past seven years, and thyroid function status. The primary endpoint is the percentage of patients experiencing at least one treatment-emergent adverse event (TEAE) or adverse event of special interest (AESI) during treatment with teprotumumab. Secondary endpoints include changes in proptosis measurement, responder rates, and quality of life assessments.
Following the screening visit, participants will be randomized to receive either teprotumumab or placebo. The trial includes multiple follow-up visits to monitor safety, efficacy, and any potential need for re-treatment. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, require immediate surgical intervention, or fail to comply with the study protocol.
Treatment
The clinical trial involves the administration of **Teprotumumab**, a lyophilized powder for preparation for injection. This experimental medication is provided by Horizon Therapeutics Ireland DAC and is identified by the sponsor product code HZN-001. The active substance, teprotumumab, is a protein of other origin. The medication is administered via infusion, with a dosage of 20 mg/kg. The maximum treatment period is 140 days. The trial aims to evaluate the safety, tolerability, and need for re-treatment of different dosing durations in patients with Thyroid Eye Disease.
The study also includes a **placebo** treatment, which consists of a normal saline (0.9% NaCl) solution. The placebo is administered in 100 mL or 250 mL infusion bags, depending on weight-based dosing volumes. This non-experimental treatment serves as a comparator to assess the effects of teprotumumab. The placebo is used to maintain the double-masked nature of the trial, ensuring unbiased evaluation of the experimental medication's efficacy and safety.
Efficacy
Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the percentage of patients who experience at least one treatment-emergent adverse event (TEAE) and the percentage of patients who experience at least one treatment-emergent adverse event of special interest (AESI) during treatment with **teprotumumab**. Additionally, the percentage of patients who receive re-treatment will be evaluated.
Secondary endpoints include several measures of symptom improvement and patient response. These include the mean change from baseline in proptosis measurement in the study eye, the proptosis responder rate, and the overall responder rate. The binocular diplopia responder rate and resolution rate will also be assessed. Patient-reported outcomes will be measured using the GO-QoL questionnaire, focusing on appearance and visual functioning sub-scales. Other secondary endpoints include the rate of flares at the end of the initial follow-up period, time to proptosis response, and changes in disease biomarkers for patients with a baseline Clinical Activity Score (CAS) of 3 or more.
Assessments will be conducted at various time points, including the end of the initial treatment period, the end of the initial follow-up period, and for patients requiring re-treatment, at the end of the 24-week re-treatment period. Safety and tolerability will be evaluated through the incidence of TEAEs, serious adverse events (SAEs), and TEAEs resulting in premature discontinuation of treatment. Additional safety assessments include the incidence of Grade 3 or higher TEAEs and laboratory evaluations, as well as best-corrected visual acuity results. Pharmacokinetic (PK) and anti-drug antibody (ADA) endpoints will be measured by peak and trough concentrations of teprotumumab and ADA incidence and titers.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent.
- Male or female between the ages of 18 and 80 years, inclusive, at Screening.
- Initial diagnosis of TED within 7 years prior to Screening.
- Initial diagnosis of TED within 7 years prior to Screening. 4. Proptosis ≥3 mm from baseline (prior to diagnosis of TED), as estimated by treating physician, and/or proptosis >3 mm above normal for race and gender (Note: For sites in France: Normal values for proptosis do vary by gender and race [de Juan et al, 1980; Fledelius and Stubgaard, 1986; Kashkouli et al, 2008]).
- Patients must be euthyroid with the baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine and free triiodothyronine levels <50% above or below the normal limits) at Screening. Every effort should be made to correct the mild hypo- or hyperthyroidism promptly and to maintain the euthyroid state for the duration of the trial.
- Does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the course of the trial.
- Diabetic patients must have HbA1c ≤8.0% at Screening.
- Patients with a history of IBD (ulcerative colitis or Crohn's disease) must be in clinical remission for at least 3 months, with no history of bowel surgery within 6 months prior to Screening and no planned surgery during the trial. Concomitant stable therapies for IBD without modifications in the 3 months prior to Screening are allowed.
- Women of childbearing potential (including those with an onset of menopause <2 years prior to Screening, non-therapy-induced amenorrhea for <12 months prior to Screening or not surgically sterile [absence of ovaries and/or uterus]) must have a negative serum pregnancy test at Screening and negative urine pregnancy tests at all protocol-specified time points (i.e., prior to each dose and throughout the patient's participation in the Follow-up Period); patients who are sexually active with a non-vasectomized male partner must agree to use 2 reliable forms of contraception during the trial, 1 of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started at least 1 full cycle prior to Baseline and continue for 180 days after the last dose of teprotumumab. Highly effective contraceptive methods (with a failure rate <1% per year), when used consistently and correctly, include implants, injectables, bilateral tubal ligation, combination oral contraceptives, some intrauterine devices, vasectomized partner or sexual abstinence. Abstinence should only be used as a contraceptive method if it is in line with the patient's usual and preferred lifestyle and periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) is not an acceptable method of contraception. Periodic abstinence, withdrawal (coitus interruptus) or spermicides only are not acceptable methods of contraception. For sites in France, highly effective contraceptive methods (with a failure rate <1% per year), when used consistently and correctly, include: • combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral intravaginal transdermal • progestogen-only hormonal contraception associated with inhibition of ovulation: oral injectable implantable • intrauterine device (IUD) • intrauterine hormone-releasing system (IUS) • bilateral tubal ligation • vasectomized partner • sexual abstinence (Abstinence should only be used as a contraceptive method if it is in line with the patient's usual and preferred lifestyle; periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] is not an acceptable method of contraception.)
- Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.
Exclusion Criteria
- Decreased best-corrected visual acuity due to optic neuropathy, as defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect or color defect secondary to optic nerve involvement within the last 6 months.
- Corneal decompensation unresponsive to medical management.
- Decrease in proptosis of ≥2 mm in the study eye between Screening and Baseline
- Prior orbital irradiation, orbital decompression or strabismus surgery.
- Planned eyelid surgery during the course of the trial.
- Alanine aminotransferase or aspartate aminotransferase >3 × the upper limit of normal or estimated glomerular filtration rate ≤30 mL/min/1.73m2 at Screening.
- Any systemic use of any steroid (intravenous [IV] or oral), or steroid eye drops for the treatment of TED or other conditions within 3 weeks prior to Screening. Such steroids cannot be initiated during the trial. Exceptions include local administration [excluding steroid eye drops], eg, topical (for skin only), intraarticular, and inhaled steroids, as well as allowance for systemic steroids (IV or oral) used to treat infusion reactions.
- Any treatment with rituximab (Rituxan® or MabThera®) within 12 months prior to the first infusion of teprotumumab or tocilizumab (Actemra® or Roactemra®) within 6 months prior to the first infusion of teprotumumab. Use of any other non-steroid immunosuppressive agent within 3 months prior to the first infusion of teprotumumab.
- Any previous treatment with teprotumumab, including previous enrollment in this trial or participation in a prior teprotumumab trial.
- Treatment with any monoclonal antibody within 3 months prior to Screening.
- Identified pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude trial participation or complicate interpretation of trial results.
- Use of an investigational agent for any condition within 60 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial.
- Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
- Pregnant or lactating women.
- Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the patient.
- Known hypersensitivity to any of the components of teprotumumab or prior hypersensitivity reactions to monoclonal antibodies.
- Human immunodeficiency virus, untreated or positive viral load for hepatitis C or hepatitis B infections
- Any other condition that, in the opinion of the Investigator, would preclude inclusion in the trial.
- After 150 patients with a CAS <3 at Baseline have been randomized, an additional exclusion criterion will apply: CAS <3 at Baseline.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 02 Jun 2021 | 30 |
 Germany | Not Recruiting | 02 Jun 2021 | 61 |
 Italy | Not Recruiting | 02 Jun 2021 | 63 |
 Spain | Not Recruiting | 02 Jun 2021 | 60 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Teprotumumab | Test | LYOPHILIZED POWDER FOR PREPARATION FOR INJECTION (8) | INFUSION | 20 | 140 | PRD10410992 |
Placebo will consist of a normal saline (0.9% NaCl) solution and will be administered in 100 mL or 250 mL infusion bags, as appropriate, per weight-based dosing volumes. | Placebo | N/A | — | — | — | N/A |