A Phase 3, Randomized, Double-masked, Placebo-controlled, Parallel-group, Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous Teprotumumab in Participants with Moderate-to-Severe Active Thyroid Eye Disease
A Phase 3, Randomized, Double-masked, Placebo-controlled, Parallel-group, Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous Teprotumumab in Participants with Moderate-to-Severe Active Thyroid Eye Disease
Michael Karon
Horizon Therapeutics U.S.A., Inc.
1 Horizon Way Deerfield, IL 60015, USA
18664796742
clinicaltrials@horizontherapeutics.com
Kojima Takashi
CMIC Co., Ltd.
1-1-1, Shibaura, Minato-ku, Tokyo
+81-80-8870-2446
ClinicalTrialInformation@cmic.co.jp
Recruiting
Aug. 30, 2024
10
Interventional
randomized controlled trial
double blind
placebo control
parallel assignment
treatment purpose
1. Participant must provide written informed consent.
2. Participant can be male or female and must be between the ages of 18 and 80 years, inclusive, at Screening.
3. Participant must have a clinical diagnosis of Graves' disease associated with active TED with a CAS >= 3 (on the 7-item scale) for the most severely affected eye at Screening and Baseline.
4. Participant must have moderate-to-severe active TED (not sight-threatening but has an appreciable impact on daily life), usually associated with 1 or more of the following: lid retraction >= 2 mm, moderate or severe soft tissue involvement and/or inconstant or constant diplopia. (Note: Participants with no diplopia at Baseline will be limited to approximately 25% of the total number enrolled.)
5. Participant has proptosis >= 18 mm at the Screening and Baseline Visits.
For sites in France: Normal values for proptosis vary by gender and race [De Juan et al, 1980; Fledelius and Stubgaard, 1986; Kashkouli et al, 2008].
6. Participant had onset of active TED symptoms (as determined by participant records) within 15 months prior to Baseline.
7. Participants must be euthyroid with the baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine [FT3] 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 full duration of the trial.
8. Participant does not require immediate surgical ophthalmological intervention and is not planning corrective surgery/irradiation during the trial.
9. 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 (ie, prior to each dose and throughout participation in the trial). Note: A high follicle-stimulating hormone (FSH) level in the postmenopausal range (> 40 IU/L) may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of non-therapy-induced amenorrhea, confirmation with more than one FSH measurement within the postmenopausal range (> 40 IU/L) is required. Females on HRT and whose menopausal status is in doubt will be required to use a nonestrogen hormonal highly effective contraception method if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment. Women of childbearing potential 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 IP (female participants should avoid donating eggs for 180 days after the last dose of IP). Highly effective contraceptive methods (failure rate < 1% per year), when used consistently and correctly, include implants, injectables, combination oral contraceptives, some intrauterine devices, tubal ligation, sexual abstinence and vasectomized partner. Abstinence should only be used as a contraceptive method if it is in line with the participant's usual and preferred lifestyle and periodic abstinence (eg, 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.
10. Participant is willing and able to comply with the protocol requirements for the duration of the trial.
1. Participant has decreased best-corrected visual acuity due to optic neuropathy, defined by a decrease in vision of 2 lines on the Snellen chart (or equivalent), new visual field defect or color defect secondary to optic nerve involvement within the last 6 months.
2. Participant has corneal decompensation unresponsive to medical management.
3. Participant has a decrease in CAS of >= 2 points between Screening and Baseline.
4. Participant has a decrease in proptosis of >= 2 mm between Screening and Baseline.
5. Participant had prior orbital irradiation, orbital decompression or strabismus surgery (excluding childhood strabismus surgeries unrelated to TED/Graves' disease).
6. Participant is planning to have eyelid surgery during the trial.
7. Participant received periocular botulinum toxin injection within 12 months prior to Screening.
8. Participant has any systemic use of a steroid (IV or oral) or steroid eye drops for the treatment of TED or other conditions within 3 weeks prior to Screening. Exceptions include local administration (excluding periocular), eg, topical, intra-articular, and inhaled steroids, as well as steroids used to treat infusion reactions.
9. Participant has used selenium within 3 weeks prior to Screening (selenium must not be restarted during the trial); however, taking a multivitamin that includes selenium (< 100 mcg daily) is allowed.
10. Participant had any previous treatment with rituximab (Rituxan or MabThera) within 12 months prior to the first administration of IP, tocilizumab (Actemra or Roactemra) within 6 months prior to the first administration of IP or any non steroid immunosuppressive agent within 3 months prior to the first administration of IP.
11. Participant has Screening laboratory samples that show any of the following abnormal results:
- Alanine aminotransferase or aspartate aminotransferase >= 3 x the upper limit of normal;
- Estimated glomerular filtration rate <= 30 mL/min/1.73 m2.
12. Participant with an HbA1c >= 7.5 at Screening.
13. Participant has pre-existing ophthalmic disease that, in the judgment of the Investigator, would preclude trial participation or complicate interpretation of trial results.
14. Participant has any history of malignancy unless it has been curatively treated and has not recurred for at least 5 years prior to Screening.
15. Participant with IBD (ulcerative colitis or Crohn's disease) who has active inflammatory intestinal or extra-intestinal symptoms, started or had a change in medical therapy within 3 months prior to Screening, had bowel surgery within 6 months prior to Screening or plans to have bowel surgery during the trial will be ineligible for the trial.
16. All participants will undergo testing for hepatitis B, hepatitis C and HIV status. Those participants positive for hepatitis B surface antigen (HBsAg) are not eligible. Those participants negative for HBsAg and positive for hepatitis B core antibody (HBcAb) will be reflex tested for hepatitis B surface antibody (HBsAb). If HBsAb is negative, the participant is not eligible for the study; if HBsAb is positive, the participant may be enrolled if allowed per local guidelines. Those participants negative for HBsAg, positive for HBcAb and HBsAb are not eligible. Those participants negative for HBsAg, negative for HBcAb and positive for HBsAb for which the cause can be determined as vaccination are eligible. If Investigator cannot be determined as vaccination, participants are not eligible. Those with detected sensitivity on hepatitis C virus (HCV) RNA quantitative test for positive HCV antibody or positive human immunodeficiency virus (HIV)-1/HIV-2 antibody are not eligible.
17. Participant is female and pregnant or breastfeeding (lactating).
18. Participant has current drug or alcohol abuse, or history of either, within the previous 12 months.
19. Participant has known hypersensitivity to teprotumumab, its excipients, medical adhesives or prior hypersensitivity reactions to mAbs.
20. Participant has previously received teprotumumab or previously participated in a teprotumumab clinical trial.
21. Participant has previously received any anti-insulin like growth factor receptor mAb.
22. Participant has previously received any investigational drug within 60 days or 5 half lives, whichever is longer, prior to Screening.
23. Participant has any other condition that, in the opinion of the Investigator, would make the participant unsuitable for inclusion in the trial.
18age old over
80age old under
Both
moderate-to-severe active TED
Approximately adult participants with active TED who meet the trial eligibility criteria will be randomized on Day 1 in a 1:1 ratio to receive SC injections of teprotumumab or placebo . Up to 25% of participants with no diplopia at Baseline may be enrolled. The randomization will be stratified by presence of diplopia at Baseline (yes vs. no), tobacco use status (yes vs. no) and region (Japan vs. non-Japan). All participants will enter a 24 week Double-masked Treatment Period.
Proptosis responder rate (percentage of participants with a >= 2-mm reduction from Baseline in proptosis in the study eye without deterioration [>= 2 mm increase] of proptosis in the fellow eye) at Week 24
- Mean change from Baseline at Week 24 in proptosis measurement in the study eye
- Overall responder rate (percentage of participants with >= 2-point reduction in CAS AND >= 2-mm reduction in proptosis from Baseline, provided there is no corresponding deterioration [>= 2-point/mm increase] in CAS or proptosis in the fellow eye) at Week 24
- Percentage of participants with a CAS value of 0 or 1 at Week 24 in the study eye
- Change from Baseline at Week 24 in diplopia as ordinal response categories
- Diplopia responder rate, defined as the percentage of participants with Baseline binocular diplopia > 0 who have a reduction of >= 1 grade at Week 24
- Complete diplopia responder rate, defined as the percentage of participants with a Baseline binocular diplopia score > 0 and a score of 0 at Week 24
- Mean change from Baseline at Week 24 in the GO-QoL questionnaire overall score
