A study to investigate efficacy and safety of OG-6219 twice a day in 3 dose levels compared with Placebo in participants aged 18 to 49 with moderate to severe endometriosis-related pain

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Organon LLC

Participant type

Patients

Age range

18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

5 Feb 2024 → 28 May 2025

Decision date (initial)

2023-05-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Organon LLC.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Pharmacokinetic

-To evaluate the efficacy of 3 dose levels of OG-6219 (Group A,B,C) versus Placebo (Group D) in reducing Overall Pelvic Pain (endometriosis related) (OPP) during Treatment Cycle 3 (TRC3), as measured by a Numeric Rating Scale (NRS) in the eDiary.
-To evaluate the safety and tolerability of OG-6219

Secondary objectives 15

1. To evaluate the efficacy of 3 dose levels of OG-6219 (GROUP A,B and C) versus Placebo (GROUP D) in reducing dysmenorrhea (DYS) during TRC3, as measured by a NRS in the eDiary
2. To evaluate the efficacy of 3 dose levels of OG 6219 (GROUP A,B,C) versus Placebo (GROUP D) in reducing non-menstrual pelvic pain (NMPP) during TRC3, as measured by a NRS in the eDiary
3. To evaluate the efficacy of 3 dose levels of OG 6219 (Group A, B, C) versus Placebo (Group D) reducing dyspareunia during TRC3, as measured by a NRS in the eDiary
4. To evaluate the daily use of Sponsor provided rescue medication taken for Endometriosis-related pain ERP at TRC1, TRC2, and TRC3
5. To evaluate the change in PGI-S Score at different time points
6. To evaluate the change in the PGI-C Score in different time points
7. To evaluate the change in the EHP 30 domains (pain, control, and powerlessness, emotional well-being, social support, and self-image) from BC to TRC3
8. To assess the incidence of clinically significant changes from V1 to V7 in bone biomarkers: o Bone resorption: C-telopeptide of Type I Collagen (CTX) N-telopeptide of Type I Collagen NTX, and Tartrate-resistant acid phosphatase 5b (TRAP5b) o Bone formation: Procollagen Type I N-terminal propeptide (P1NP), Bone-specific alkaline phosphatase (BSAP), and osteocalcin
9. To assess the incidence of any clinically significant changes in laboratory parameters from V1 to V5, V6, V7, and V8
10. To assess vaginal bleeding pattern over the 3 menstrual cycles (TRC1, TRC2, and TRC3) as captured in the eDiary
11. To assess any potential change in the Electrocardiogram (ECG) parameters at V4, V5, V6, and V7
12. To assess the change from V1 to V7 in serum hormone concentrations
13. To assess any difference in serum hormone concentrations at V5 between active treatment versus placebo
14. To assess any difference in serum hormone concentrations at V7 between active treatment versus placebo
15. To assess the PK of orally administered OG-6219 and the active metabolite FOR-1011 using sparse and intensive PK sampling

Conditions and MedDRA coding

Endometriosis related pain

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-003537-PIP01-23

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Pre-menopausal females of age 18 to 49 years old (inclusive) at the time of signing Informed Consent (V1).
2. Surgically (laparoscopy or laparotomy) diagnosed with endometriosis within the last 4 months to 10 years prior to Screening Visit (V1), as documented by medical records
3. Has moderate to severe endometriosis-related pelvic pain in recent menstrual cycle(s) using a cutoff score of ≥4 in a numeric rating scale (NRS) and likely meets eligibility criterion # 10 at Randomization Visit (V4)
4. Has had spontaneous (ie, without hormonal therapy), regular, menstrual cycle with a cycle length between 21 to 32 days (inclusive) for the past 1 month before V1
5. Is not expected to undergo a planned gynecological surgery or other surgical procedures for treatment of endometriosis during study participation.
6. Has a normal breast examination at V1. In participants of ≥40 years mammography or contrast-enhanced breast magnetic resonance imaging (MRI) performed within the last 12 months prior to Screening (V1) without clinically significant abnormal findings.
7. Agrees not to participate in another interventional study while participating in the present study.
8. Is able and willing (in the opinion of the Investigator) to adhere to all required study procedures, including: a) Study visits schedule, b) Agree to switch from their usual analgesic to ONLY the rescue medication provided by the study and agree to discontinue their hormone treatment for ERP as outlined in Table 2 of the protocol. c) Agree to timely and duly complete eDiary entries, d) To cooperate and comply with the protocol requirements, including, Transvaginal ultrasound (TVUS), ECG, PK, and pharmacodynamic (PD) assessment among others. e) Agree to use 2 forms of non-hormonal contraception throughout the study (from V1 thorough V8). f) Not planning to relocate during the study (such that the participant would not be able to continue participation at the study site).
9. Must be willing and able to provide signed informed consent before any study-related activities.
10. At Visit 4: Has moderate to severe ERP, determined by the NRS (0 to 10 anchored, with 0 [no pain] and 10 [extremely severe pain]), at V4 (before Randomization), based on the eDiary entries from the participant’s last menstrual cycle (BC), as follows: a) An OPP (DYS and NMPP) score of ≥4, OR b) For DYS at least 2 days with ≥4 and NMPP score of ≥4 on at least 7 days (not necessarily consecutive), OR c) For DYS at least 2 days with ≥4 and NMPP score of ≥7 on at least 3 days (not necessarily consecutive).
11. At Visit 4: Has demonstrated compliance with ≥75% of eDiary entries (ie, pelvic pain score, vaginal bleeding, rescue medication intake) during both the screening cycle (SC) and the BC.
12. At Visit 4: Is ≥80% compliant with the Placebo tablets over the BC (Placebo Run-in), as determined by tablet accountability at the site.
13. At Visit 4: Has taken only the study provided rescue medication, at a dose not exceeding the maximum dose determined by the Investigator, for control of ERP during the BC as evidenced in the eDiary.
14. Have a negative pregnancy test as outlined in the Schedule of activity of the protocol

Exclusion criteria 31

1. Has a surgical history of hysterectomy and/or bilateral oophorectomy.
2. Has chronic pelvic and/or non-pelvic pain NOT CAUSED by endometriosis that requires chronic analgesic or other chronic therapy (including, but not limited to, pain caused by interstitial cystitis, bladder pain syndrome, irritable bowel syndrome, hysteroscopic sterilization, adenomyosis [as confirmed by previous MRI], vaginismus, chronic pelvic infection, fibromyalgia, chronic headaches, chronic back pain). Participants using or who will be using frequent opioid analgesics, cannabis, or non-opioids analgesics for chronic pain or recurring pain other than that due to ERP should also be excluded.
3. Has a clinically significant gynecologic condition identified in the screening (including, but not limited to, endometriomas larger than 4 cm, complex ovarian cysts larger than 3 cm, simple ovarian cysts larger than 5 cm, single fibroid larger than 4 cm, symptomatic submucosal fibroid of any size, polyp >2 cm, hyperplasia, or endometrial cancer or any clinically significant endometrial pathology).
4. Has a history of ERP that was not responsive at all (refractory) to treatment with CHCs, GnRH agonists and antagonists, progestins, or aromatase inhibitors alone or in combination. The participant that required >2 weeks of continuous use of narcotics for treatment of ERP within 6 months of V1 should also be excluded.
5. Had undiagnosed (unexplained), abnormal, vaginal bleeding not associated with the baseline condition (endometriosis) within the past 6 months before screening.
6. Has an active sexually transmitted infection (STI) (eg, gonorrhea, chlamydia, or trichomonas) is exclusionary
7. Has no documented normal Papanicolaou (PAP) test within the timeline of current standard of care guidelines or has a significantly abnormal PAP test at Screening (V1) (low grade squamous intraepithelial lesion, high grade squamous intraepithelial lesion, atypical glandular cells [any type], squamous cell carcinoma, or adenocarcinoma [in situ or invasive]). The presence of high-risk human papillomavirus (HPV), regardless of PAP result, is exclusionary (e.g. atypical squamous cells)
8. Intends to become pregnant during study participation or has a known or suspected pregnancy or has a positive β hCG or urine pregnancy test at any time before randomization.
9. Has a history of malignancy (except basal cell or squamous cell skin cancer) before signing informed consent. Note: Any history of hormonal sensitive malignancy (e.g., breast or ovarian cancers) excludes the participant
10. Has a history or family history of a hereditary abnormal hemoglobin or an enzyme deficiency that can result in methemoglobinemia (with an alteration in skin; color, pale, gray, or blue), or after receiving certain common drugs (ie, benzocaine, lidocaine, sulfonamides).
11. Has a medical condition associated with hemolytic anemia such as sickle cell anemia, thalassemia, glucose-6-phosphate dehydrogenase deficiency, thrombotic thrombocytopenic purpura among other conditions previously diagnosed and confirmed.
12. Has an allergy/sensitivity/intolerance to rescue medication provided by Sponsor or any contraindication to its use and in the setting of coronary artery bypass grafting surgery, or has experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other Nonsteroidal anti-inflammatory drug (NSAIDs)
13. Has a history or current evidence of any unstable medical condition (including cardiovascular, bone, musculoskeletal, thyroid, diabetes), or other circumstance that in the opinion of the Investigator might confound the results of the study, affect participant’s safety or well-being, or interfere with the participant’s participation for the full duration of the study
14. Has a known human immunodeficiency virus infection, and/or an acute or active, recurrent/relapsing or chronic infection (eg, hepatitis A, B, or C virus)
15. Has a gastrointestinal, liver, kidney, or other disorder that would significantly interfere with the absorption, distribution, metabolism, or excretion of drugs in the opinion of the Investigator
16. Has a clinically significant abnormal ECG or QT interval prolongation at Screening Visit (V1) or Randomization Visit (V4). Any participant with the following conditions must be excluded: a) A marked baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval >450 milliseconds) b) A history of additional risk factors for Torsade de Pointes (eg, heart failure, hypokalemia, family history of Long QT Syndrome) c) Use of concomitant medications that prolong the QT/QTc interval (such as but not limited to: ibutilide, quinidine, imipramine, erythromycin, and droperidol).
17. Plans to schedule elective surgery during the study execution or had surgery in the past 4 months before screening that continues to require pain management.
18. Suspected active Coronavirus Disease 2019 (COVID-19) infection a) Have tested positive for severe acute respiratory syndrome–related coronavirus 2 (SARS-CoV-2) based on a validated test per local guidelines at Screening and Baseline b) Have to comply with quarantine requirements per local Public Health directive
19. Has been vaccinated with live or live-attenuated virus vaccine within 30 days prior to Screening
20. Has an uncontrolled hypertension as diagnosed by participant’s treating physician.
21. Has any of the following abnormal laboratory values at Screening a)Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma glutamyl transpeptidase >2 × upper limit of normal (ULN) Alkaline Phosphatase >1.5 × ULN, provided cholestatic or other liver disease is excluded b) Total bilirubin (TBL) >1.0 × ULN (participants with Gilbert’s syndrome can be enrolled if other liver function tests are within stated limits)c) Impaired renal function as indicated by estimated glomerular filtration rate <30 mL/min/1.73 m2 (CKD-EPI 2009 calculation) d)Hemoglobin <10 gm/dL, white blood cell count <2500 mm3, neutrophil count <1500 mm3, platelet count <100 × 103/mm3.
22. Based on the known metabolism of OG-6219 there are no effects of alcohol, caffeine, or tobacco associated with study treatment. However, during the study participants are asked to refrain from: a) Excessive tobacco use and smoking (including cannabis-derived and cannabis-related compounds based on Investigator’s discretion). Note: Short term use (ie, ≤ 3 days per cycle) of cannabis-derived and cannabis-related compounds are permitted. b) Active use of illicit drugs and/or alcohol abuse/dependance, as determined by the Investigator.
23. Has a prior or current history of drug or alcohol abuse disorder according to Diagnostic and Statistical Manual of Mental Disorders 5 (DSM5).
24. Has undergone blood transfusion within 2 weeks of V1. In addition, has lost ≥1 unit of blood (approximately 300 mL) within 8 weeks before the first dose of OG-6219.
25. Use of treatments that might interfere with the conduct of the study or interpretation of the results
26. Used any medication listed in the protocol that is either a sensitive substrate, moderate, or strong inhibitor or inducer of CYP3A4 within 30 days or 10 half-lives (whichever is longer) prior to the planned first day of dosing. Participants must not consume other substances known to be potent inhibitors or inducers of CYP P450s such as grapefruit or Seville oranges containing products in 2 weeks before the planned first dose of study treatment administration.
27. Current or a history of psychiatric disorder in the 3 years prior to Screening that would, in the opinion of the Investigator, affect the ability to participate in the study or would impair interpretation of data. Participants with current major depression, posttraumatic stress disorder, bipolar disorder, schizophrenia, or other psychotic disorders are excluded. Participant has a history of suicidal ideation or attempt within 3 years of Screening (V1).
28. Has been a participant in an investigational drug or device study within 30 days prior to the Screening Visit.
29. A study site employee or relative of a study site employee.
30. Participant is pregnant, breast feeding, or planning a pregnancy within the next 7 months.
31. Participants has received any treatment listed in the table of Prohibited Medication and Other Substances more recently than the “Last Allowable Use”, as indicated in the table, or must continue to receive any treatment listed in that table during the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Change from BC to TRC3 in the mean OPP score
2. Proportion of participants who experienced any AEs/SAEs
3. Abnormalities in clinical laboratory assessments, vital signs, and physical examination
4. Proportion of participants who prematurely discontinued study treatment due to AEs/SAEs

Secondary endpoints 17

1. Change from BC to TRC3 the mean DYS score
2. Change from BC to TRC3 of the mean NMPP score
3. Change from BC to TRC3 in the mean dyspareunia score
4. Change from BC to TRC1, TRC2, and TRC3 in the mean number of tablets of rescue medication for ERP
5. Change from BC to TRC1, TRC2, and TRC3 in the proportion of days participant has used rescue medication for ERP
6. Change in PGI-S Score from V4 to Phone Contact 1, V6, and V7
7. Percentage of participants with any improvement in the PGI-C at TRC1, TRC2, and TRC3.
8. Change from BC to TRC3 in the EHP-30 Domain Scores
9. Mean change from V1 to V7 in bone biomarker levels
10. Proportion of participants with clinical parameters of significance from V1 to V5, V6, V7, and V8
11. Mean change from BC to TRC1, TRC2, TRC3 in the percentage of days with vaginal bleeding
12. ECG parameter changes at V4, V5, V6, and V7
13. Main change from scoreV1 to V7 in serum hormone levels
14. Serum hormone levels comparing Group A (50 mg BID), B (100 mg BID), C (150 mg BID) with Group D (Placebo)
15. Serum hormone levels at V7 comparing Group A (50 mg BID), B (100 mg BID), C (150 mg BID) with Group D (Placebo)
16. Plasma concentrations of OG-6219 and FOR-1011 at scheduled assessments using sparse PK sampling during the treatment period.
17. Cmax, Tmax, and AUCtau for both OG-6219 and FOR-1011 on V4 and V5 for the population with intensive PK sampling

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Organon LLC

Sponsor organisation

Organon LLC

Address

30 Hudson Street

City

Jersey City

Postcode

07302-4804

Country

United States

Scientific contact point

Organisation

Organon LLC

Contact name

Elena study information desk

Public contact point

Organisation

Organon LLC

Contact name

Elena study information desk

Third parties 10

Locations

10 EU/EEA countries · 58 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 9 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 420 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

34 submissions — initial application plus substantial / non-substantial modifications