Dorzagliatin for people with cystic fibrosis and pancreatic insufficiency

Pharmacokinetic and Pharmacodynamic Effects of Dorzagliatin in Pancreatic Insufficient-Cystic Fibrosis: A Randomized Double-blind, Cross-over Trial

This study will test whether taking dorzagliatin twice daily for 7 days improves blood sugar control in adults with cystic fibrosis, pancreatic insufficiency, and abnormal glucose tolerance compared with placebo.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 15 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Pennsylvania (Academic / other)
• Locations: 2 sites (Philadelphia, Pennsylvania and 1 other locations)
• Trial ID: NCT06995651 on ClinicalTrials.gov

What this trial studies

This is a randomized, double-blind, placebo-controlled, crossover Phase 1 trial of dorzagliatin 50 mg given twice daily for 7 days in adults with cystic fibrosis and pancreatic insufficiency who have abnormal glucose tolerance or CFRD. Participants will receive dorzagliatin and placebo in separate treatment periods with washout between periods, and investigators will measure drug concentrations and glucose-related responses. Key pharmacodynamic measures include glucose tolerance during a standardized mixed-meal tolerance test, early-phase insulin secretion, glucagon suppression, and markers of hepatic glycogen storage. The study is conducted at the University of Pennsylvania clinical research sites and focuses on short-term safety and metabolic effects in this specific patient group.

Who should consider this trial

Good fit: Adults (≥18 years) with confirmed cystic fibrosis and pancreatic insufficiency who have abnormal glucose tolerance or CFRD, who meet the study’s lab and contraception requirements, and who can attend visits at the Philadelphia study center are eligible.

Not a fit: People without cystic fibrosis or pancreatic insufficiency, those with uncontrolled diabetes outside the study’s allowable HbA1c/C‑peptide ranges, pregnant people, or those unable to travel to the study site are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, dorzagliatin could improve short-term glucose control and insulin secretory responses in people with cystic fibrosis–related glucose abnormalities.

How similar studies have performed: Dorzagliatin and other glucokinase activators have shown glucose‑lowering effects in type 2 diabetes, but using dorzagliatin in people with cystic fibrosis and pancreatic insufficiency is novel and has not been established.

Eligibility criteria

Inclusion Criteria:

1. Provision of signed and dated informed consent form.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Male or female, aged ≥18 years on date of consent.
4. Confirmed diagnosis of CF, defined by positive sweat test or CFTR mutation analysis according to CFF diagnostic criteria.
5. Pancreatic insufficiency defined by clinical requirement for pancreatic enzyme replacement.
6. Abnormal glucose tolerance defined by OGTT criteria for EGI, IGT, or CFRD, or diagnosed CFRD.
7. There will be no restriction on enrollment of individuals with CFRD but without fasting hyperglycemia (fasting hyperglycemia is defined as fasting glucose ≥126 mg/dL)

   a. Individuals with CFRD and fasting hyperglycemia (defined as above or by the use of basal insulin therapy) must also have a HbA1c ≤8% and a random (non-fasting) C- peptide ≥1.2 ng/mL \[15\].
8. For females of reproductive potential: use of highly effective contraception method for the during of study participation; oral contraceptives, intra-uterine devices, Norplant®, Depo- Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.

Exclusion Criteria:

1. Established diagnosis of non-CF diabetes (e.g. type 1 diabetes).
2. Pregnancy or lactation; a negative urine pregnancy test will be required at enrollment.
3. Pulmonary exacerbation requiring IV antibiotics or systemic glucocorticoids within 4 weeks prior to randomization.
4. Treatment with either CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, indinavir, ritonavir, saquinavir, telithromycin, boceprevir, nelfinavir, telaprevir, conivaptan, nefazodone, etc.) or inducers (e.g. phenobarbital, other barbiturates, carbamazepine, phenytoin, rifampicin, dexamethasone, etc.).
5. Use of herbal remedies, including St. John's Wort within 14 days prior to dosing.
6. Change in CFTR modulator therapy in the previous 3 months.
7. History of clinically symptomatic pancreatitis within the last year.
8. Prior lung, liver or another solid organ transplant.
9. Abnormal kidney function: creatinine \>2x upper limit of normal (ULN) or potassium \>5.5mEq/L on non-hemolyzed specimen.
10. Abnormal liver function: persistent elevation of liver function tests \>2.0 times ULN.
11. Uncontrolled hyperlipidemia: triglycerides \>500 or cholesterol \>250 mg/dl.
12. Hyperuricemia: serum uric acid \>1.5 times ULN.
13. Anemia: hemoglobin \<10 g/dL.
14. History of any illness or condition that, in the opinion of the investigator might confound the results of the study or pose an additional risk to the subject.

Where this trial is running

Philadelphia, Pennsylvania and 1 other locations

• Hospital of University of Pennsylvania — Philadelphia, Pennsylvania, United States (Recruiting)
• University of Pennsylvania Center for Human Phenomic Science (CHPS) — Philadelphia, Pennsylvania, United States (Recruiting)

Study contacts

• Principal investigator: Michael R Rickels, MD, MS — University of Pennsylvania
• Study coordinator: Paola Alvarado, MSCR

Conditions Pancreatic Insufficiency; Cystic Fibrosis-related Diabetes