A Study to Evaluate the Drug-Drug Interaction Between KL0011034 Injection and Alfentanil Hydrochloride Injection in Participants With Moderate-to-Severe Non-Cancer Chronic Pain

Official title

A Single-Center, Randomized, Open-Label, Three-Sequence, Three-Period Crossover Study to Evaluate the Drug-Drug Interaction Between KL0011034 Injection and Alfentanil Hydrochloride Injection in Trial Participants With Moderate-to-Severe Non-Cancer Chronic Pain

Overview

This study will evaluate the drug-drug interaction between KL0011034 Injection and Alfentanil Hydrochloride Injection in participants with moderate-to-severe non-cancer chronic pain. The study consists of two parts. Part 1 is a single-center, randomized, open-label, parallel-design study to evaluate the safety, tolerability, and pharmacodynamics of the combination. Approximately 9 participants will be enrolled and randomized to one of three dose groups (n=3 per group). Part 2 is a single-center, randomized, open-label, three-sequence, three-period crossover study to evaluate the pharmacokinetic interaction, safety, tolerability, and pharmacodynamic effects. Approximately 18 participants will be enrolled and randomized to one of three sequences (n=6 per sequence), with a 3-day washout period between each period.

Detailed description

Study Design and Population:

This is a two-part, single-center, randomized, open-label study in participants with moderate-to-severe non-cancer chronic pain. Part 1 uses a parallel-group design, and Part 2 uses a three-sequence, three-period crossover design.

Part 1 (Safety, Tolerability, and Pharmacodynamics):

Approximately 9 participants will be randomized in a 1:1:1 ratio to one of three dose groups to receive a single combined dose of Alfentanil Hydrochloride Injection 5 μg/kg plus KL0011034 Injection at one of three dose levels (Group 1: 0.3 mg/kg; Group 2: 0.35 mg/kg; Group 3: 0.4 mg/kg). Pharmacodynamic and safety evaluations will be conducted, and participants will be discharged after the end-of-study examinations on Day 2 (D2). Based on the results from Part 1, the maximum dose of KL0011034 Injection among the three dose levels that is deemed safe and tolerable will be selected for use in Part 2.

Part 2 (Pharmacokinetic Interaction, Safety, Tolerability, and Pharmacodynamics):

Approximately 18 participants will be randomized in a 1:1:1 ratio to one of three sequences (A, B, or C), with 6 participants per sequence. Each participant will complete three open-label treatment periods (Day 1, Day 4, and Day 7), with a 3-day washout period between periods. The selected KL0011034 dose from Part 1 will be used in Part 2. Pharmacokinetic sampling, pharmacodynamic evaluations, and safety assessments will be performed during each period. Participants will be discharged after the end-of-study examinations on Day 8 (D8).

Sequence A: Period 1: KL0011034 Injection (selected dose); Period 2: Alfentanil Hydrochloride Injection 5 μg/kg; Period 3: Alfentanil Hydrochloride Injection 5 μg/kg + KL0011034 Injection (selected dose).

Sequence B: Period 1: Alfentanil Hydrochloride Injection 5 μg/kg; Period 2: Alfentanil Hydrochloride Injection 5 μg/kg + KL0011034 Injection (selected dose); Period 3: KL0011034 Injection (selected dose).

Sequence C: Period 1: Alfentanil Hydrochloride Injection 5 μg/kg + KL0011034 Injection (selected dose); Period 2: KL0011034 Injection (selected dose); Period 3: Alfentanil Hydrochloride Injection 5 μg/kg.

Interventions

• Drug KL0011034 injection
  KL0011034 Injection is an investigational drug being studied for its analgesic properties in combination with alfentanil. It is administered via intravenous infusion. The dose levels evaluated are 0.3 mg/kg, 0.35 mg/kg, and 0.4 mg/kg in Part 1; the selected dose from Part 1 is used in Part 2.
• Drug Alfentanil Hydrochloride Injection
  Alfentanil Hydrochloride Injection is an opioid analgesic administered via intravenous bolus at a fixed dose of 5 μg/kg. It is used alone and in combination with KL0011034 Injection to evaluate drug-drug interaction.

Primary outcome measures

• Maximum Plasma Concentration (Cmax) of KL0011034 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours]
• Maximum Plasma Concentration (Cmax) of KL0011034 Metabolite A644S(A)-Z7 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours post-dose.]
• Maximum Plasma Concentration (Cmax) of Alfentanil [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after bolus completion, and at 1, 2, 3, 6, 11, 16, 21, 31, 41, 51, 61 minutes, and 2, 4, 8, 12, 24 hours post-dose.]
• Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of KL0011034 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours]
• Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of KL0011034 Metabolite A644S(A)-Z7 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours]
• Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of Alfentanil [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours]
• Area Under the Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of KL0011034 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours]
• Area Under the Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of KL0011034 Metabolite A644S(A)-Z7 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours]
• Area Under the Curve From Time Zero Extrapolated to Infinity (AUC0-∞) of Alfentanil [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing);immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours]

Secondary outcome measures (12)

• Time to Maximum Plasma Concentration (Tmax) of KL0011034 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours post-dose.]
• Time to Maximum Plasma Concentration (Tmax) of KL0011034 Metabolite A644S(A)-Z7 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours post-dose.]
• Time to Maximum Plasma Concentration (Tmax) of Alfentanil [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after bolus completion, and at 1, 2, 3, 6, 11, 16, 21, 31, 41, 51, 61 minutes, and 2, 4, 8, 12, 24 hours post-dose.]
• Area Under the Curve From Time Zero to 24 Hours (AUC0-24h) of KL0011034 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours post-dose.]
• Area Under the Curve From Time Zero to 24 Hours (AUC0-24h) of KL0011034 Metabolite A644S(A)-Z7 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours post-dose.]
• Area Under the Curve From Time Zero to 24 Hours (AUC0-24h) of Alfentanil [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after bolus completion, and at 1, 2, 3, 6, 11, 16, 21, 31, 41, 51, 61 minutes, and 2, 4, 8, 12, 24 hours post-dose.]
• Elimination Half-Life (t1/2) of KL0011034 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours post-dose.]
• Elimination Half-Life (t1/2) of KL0011034 Metabolite A644S(A)-Z7 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours post-dose.]
• Elimination Half-Life (t1/2) of Alfentanil [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after bolus completion, and at 1, 2, 3, 6, 11, 16, 21, 31, 41, 51, 61 minutes, and 2, 4, 8, 12, 24 hours post-dose.]
• Apparent Volume of Distribution (Vd) of KL0011034 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours post-dose.]
• Apparent Volume of Distribution (Vd) of KL0011034 Metabolite A644S(A)-Z7 [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after infusion completion, and at 2, 5, 10, 15, 20, 30, 40, 50 minutes, and 1, 2, 4, 8, 12, 24 hours post-dose.]
• Apparent Volume of Distribution (Vd) of Alfentanil [Time frame: Part 2, each of the 3 treatment periods (Day 1, Day 4, Day 7): pre-dose (within 60 minutes before dosing); immediately after bolus completion, and at 1, 2, 3, 6, 11, 16, 21, 31, 41, 51, 61 minutes, and 2, 4, 8, 12, 24 hours post-dose.]

Eligibility criteria

Inclusion criteria

• Those who fully understand the purpose, content, process and possible risks of the trial, and voluntarily participate and sign the informed consent form;
• Male and female patients with moderate to severe non-cancerous chronic pain (such as patients with shoulder inflammation, chronic back pain, myofascial pain syndrome) aged between 18 and 55 years (inclusive of the boundary values), with a NRS score of >= 4;
• Male weight not less than 50.0 kg, female weight not less than 45.0 kg; Body Mass Index (BMI) within the range of 19.0 to 26.0 kg/m2 (including the critical value);
• From the date of signing the informed consent form to the last administration of the trial medication within 3 months, the trial participants (and their partners) have no plans for conception, and the trial participants have no plans for sperm donation/egg donation; From the date of signing the informed consent form to the completion of the exit examination, the participants voluntarily adopt non-pharmacological contraceptive measures; After the exit examination to the last 3 months after the last administration of the trial medication, the participants voluntarily adopt effective contraceptive measures;
• Able to communicate well with the researchers, willing and able to comply with the lifestyle restrictions stipulated in the protocol, and cooperate to complete the trial process.

Exclusion criteria

• Known to be allergic to alfentanil or other opioid analgesics, etomidate or other anesthetic drugs, or to be of allergic constitution (such as allergy to two or more drugs, food or pollen), or prone to develop rashes, urticaria, etc., or having a history of allergic diseases, or known to be allergic to the excipients or raw materials of this product;
• Having a history of head trauma, possible intracranial hypertension, cerebral aneurysm, cerebrovascular accident, or mental illness such as schizophrenia, mania, bipolar disorder, mental confusion, long-term use of psychotropic drugs or cognitive dysfunction;
• Having a history of serious cardiovascular diseases (such as hypertension, heart failure, severe arrhythmia, etc.) and/or heart diseases, family history of heart disease and/or unstable angina pectoris, or having had a myocardial infarction in the past 6 months;
• Having a history of other cardiovascular, endocrine, respiratory, digestive, urinary, nervous, hematological and/or lymphatic system diseases, and the investigator considers that it still has clinical significance during the screening;
• Having a history of anesthesia accidents, severe adverse reactions during anesthesia or family history of anesthesia accidents, or having contraindications for general anesthesia;
• Having difficulty breathing or suspected difficult airway or estimated difficulty in tracheal intubation (such as modified Mallampati score grade III-IV, congenital small tongue, maldevelopment of mandible, etc.);
• Having a history of airway diseases such as bronchial asthma, chronic obstructive pulmonary disease, sleep apnea syndrome, etc.;
• Having a history of adrenal insufficiency, adrenal tumor or hereditary hemoglobin biosynthesis disorder or hereditary acute porphyria;
• Having a surgical history within 3 months before screening, or not recovering from surgery, or having planned surgery during the trial;
• Having conditions, surgical history, diseases related to the use of the test drug, or any other special circumstances that may significantly affect drug absorption, distribution, metabolism and excretion;
• Abnormal results of physical examination, vital signs, full thoracic radiograph, abdominal B-ultrasound, laboratory tests (blood routine, urine routine, blood biochemistry, coagulation function) have clinical significance;
• Having clinically significant electrocardiogram abnormalities found during screening, such as QTcF >=450 ms (male) or >=460 ms (female), etc.;
• Positive for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), human immunodeficiency virus antibody (HIV-Ab), and syphilis spirochete antibody (TP-Ab);
• Having unprotected sexual behavior within 2 weeks before the first administration of the test drug;
• Female subjects during the screening period are in pregnancy or lactation, or have a positive pregnancy result;
• Having a history of drug abuse or drug dependence within the past 1 year, or having a positive urine drug screening at the time of screening;
• Having a history of alcohol abuse within 6 months before screening \[that is, consuming more than 14 standard units of alcohol per week (1 unit = 360 ml of beer or 45 ml of 40% alcohol liquor or 150 ml of wine)\], or being unwilling to stop drinking alcohol or any alcoholic products during the trial, or having a positive alcohol breath test at the time of screening;
• Having a history of smoking within 3 months before screening (daily smoking quantity >= 5 cigarettes), or being unwilling to stop using any tobacco products during the trial, or having a positive smoke test result at the time of screening;
• Having consumed excessive (8 cups or more, 1 cup = 250 ml) tea, coffee or caffeine-containing beverages (such as milk tea, cola, etc.) every day within 14 days before screening, or being unwilling to stop drinking these beverages during the trial;
• Individuals who consumed grapefruit/grapefruit juice, foods or beverages rich in xanthine components (such as shiitake mushrooms, white carp, black carp, whelk, white bream, oysters, white snapper, sea eel, duck liver, chicken liver, pork intestines, pork liver, beef liver, etc.) within 48 hours before the first administration of the test drug, or those who had any special diet that could affect the absorption, distribution, metabolism, or excretion of the drug;
• Individuals who had used any medication within 14 days before the first administration of the test drug, including prescription drugs, over-the-counter drugs, traditional Chinese medicines, health supplements, and vitamins;
• Individuals who had used inhibitors or inducers of CYP3A4 or CYP2C19 (such as CYP3A4 inhibitors: sirivatinib, atalenti, edalizumab, telifast, clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, indinavir, nelfinavir, ritonavir, sapparin, tipranavir, lopinavir, nafamoxin, cobizumet; CYP3A4 inducers: apalutamide, enzalutamide, rumactat, mitotane, evolizumab, phenytoin, carbamazepine, rifampicin, St. John's wort; CYP2C19 inhibitors: fluvoxamine, fluconazole, fluoxetine, ticlopidine, phenabarbital, nalfurafine, voriconazole; CYP2C19 inducers: rifampicin, apalutamide, efavirenz, enzalutamide, phenytoin) within 1 month before the first administration of the test drug;
• Individuals who had been using sedative drugs and/or opioid analgesics for more than 3 months before screening;
• Individuals who had participated in any clinical trials and used the test drug/medical device within 3 months before the first administration of the test drug, or were still in the follow-up period of other trials;
• Individuals who had received inactivated vaccines within 1 month before screening, or received live/deleted vaccines within 3 months before screening, or planned to receive inactivated/live/deleted vaccines during the trial;
• Individuals who had undergone blood loss or blood donation or transfusion or received a total amount of blood products exceeding 400 ml within 3 months before screening, or planned to donate blood or undergo surgery within 1 month after the trial or after the trial ends;
• Individuals with difficulty in blood collection, or those who cannot tolerate venipuncture, or those with a history of fainting or needle shock;
• Individuals with poor compliance, or other situations that the researcher deems unsuitable for participation in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07751094 · KL0011034-102

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗