Design
The present study is a single-centre, randomized, open-label controlled trial in postmenopausal population with OP. Postmenopausal OP patients will admit to the outpatient department of Peking University Third Hospital will be enrolled in this trial. After signing the informed consent form, they will be randomly divided into four groups: the alendronate-old women (<75 years old), alendronate-senior women (≥75 years old), minodronate-old women (<75 years old), and minodronate senior women (≥75 years old) groups. The sealed envelopes methods were used for randomization. The clinical research coordinator will generate the allocation sequence, enrol participants, and assign participants to interventions. The old groups consisted of 24 patients in each group, and the senior groups consisted of 12 patients in each group. The subjects in the four groups will be orally treated with alendronate and minodronate daily for 12 weeks, and drug administration will be stopped after 12 weeks. The entire experiment is divided into two stages: the first stage is 12 weeks, and the second stage is 12 weeks. The efficacy of minodronate in the treatment of low back pain is mainly evaluated by the VAS score and the frequency and dose of rescue medication administered. The safety assessment is mainly based on the occurrence of fractures after administration and the occurrence of gastrointestinal adverse reactions after oral administration.
Patient and public involvement
Patients or the public will not be involved in the design, conduct, reporting, or dissemination plans of this study.
Eligibility criteria
Inclusion criteria
- Chinese postmenopausal patients with a diagnosis of OP;
- Patients with low back pain of at least 3 months and a VAS score ≥30;
- The value of lumbar L1-4 or total hip bone density measured by DXA is ≤-2.5;
- Serum 25-hydroxyvitamin D (25-OHD) concentration ≥20 ng/mL;
- Patients with full capacity for civil conduct and understanding of the research process and methods voluntarily participated in this study and signed the informed consent form.
Exclusion criteria
- Patient who are allergic to minodronate, alendronate, or other bisphosphonates or any other component of the drug under evaluation;
- Patients with a diagnosis of secondary OP;
- The following drugs affecting bone metabolism were used before the screening:
Received injections of bisphosphonates and denosumab within 3 years;
Received oral bisphosphonates, parathyroid hormones or analogues, strontium, or fluoride within 6 months;
Received glucocorticoids, steroids, immunosuppressants, calcitonin, calcitriol or its analogues, thiazide diuretics, and oestrogen/progesterone replacement therapy within 3 months;
- Patients with a diagnosis of diseases affecting bone metabolism (e.g., osteogenesis imperfecta, malignancy, progressive diaphyseal dysplasia, Paget's disease, rheumatoid arthritis, osteosclerosis, osteoporosis with a slipped disc and spinal stenosis, and liver and kidney failure);
- Patients are participating or have participated in an investigational drug study within 3 months before signing the informed consent form;
- Patients under 75 years old with a creatinine clearance rate < 60 mL/min and those higher than 75 years old with a creatinine clearance rate < 45 mL/min;
- Serum calcium levels < 2.0 mmol/L (8 mg/dL) or > 2.7 mmol/L (11.0 mg/dL);
- Patients with fever, severe infection, severe trauma, or major surgery within 30 days;
- Patients with a QTc interval of > 480 ms;
- Patients are undergoing or planning to undergo invasive dental treatment;
- Smoking history in the past six months;
- Patients with a history of alcohol abuse (> 15 g of alcohol per day, equivalent to 350 mL of beer or 150 mL of wine, more than twice per week) and drug abuse;
- Patients with a prior history of cerebral infarction, ischaemic or haemorrhagic stroke;
- Patients with implants and/or fractures in the lumbar spine or hip that interfere with BMD testing;
- Received pain relievers (e.g., nonsteroidal anti-inflammatory drugs, central analgesics) or life interventions to relieve pain within 1 week before screening;
Withdrawal criteria
Participants will be free to withdraw their informed consent and withdraw from the study. The investigator may withdraw the participant from the study under any of the following conditions:
1) Participants withdraw consent.
2) Serious changes in clinical or laboratory examination results occur during the study that would be detrimental to the subject’s health care as observed by the investigator.
3) Participants who exhibit poor compliance, refuse to undergo all required tests, and cannot adhere to the study plan;
4) Participants who are unable to attend the follow-up or dropped out.
Interventions:
The minodronate group: The group will include thirty-six patients. Patients will take 1 mg of minodronate tablets orally with 200 mL of water in the morning. They can not lie flat for at least 30 minutes after taking the tablets, and they can not eat anything except water for at least 30 minutes after taking the tablets once a day for 12 weeks, for a total of 84 times.
The alendronate group: A total of 36 patients will be treated with alendronate. Patients will be orally given 10-mg alendronate tablets daily and 200 mL of water in the morning. They could not lie down and eat anything except water for at least 30 minutes after taking the tablets. The treatment lasted for 12 weeks, corresponding to a total of 84 doses.
Calcium and vitamin D: The presence of polyvalent cations can result in the formation of polyvalent cations and complexes, which can affect the absorption of the test drug when take together with minodronate and alendronate. Therefore, all patients will receive oral calcium supplementation and vitamin D after dinner throughout the study period.
Rescue medicine: During the trial, if the patients take the test drug (minodronate) and the control drug (alendronate), the low back pain suddenly will worsen, the pain VAS score is still more than 70, and the patients can not tolerate the pain, they will be uniformly treated with rescue medicine (acetaminophen), and the pain relief time should not exceed 5 days. During this period, patients will be required to fill in the VAS score form and the frequency and dose of rescue medication in the diary booklet.
Concomitant care: During the screening, the patients’ past pain relief methods, such as pain medication or the way of life intervention will be recorded. The use of the above methods during the patients’ treatment will be prohibited to prevent interference with the results of the clinical trials.
Adherance: During the screening and informed consent period, the subjects shall be informed and reminded to ensure that the subjects are fully informed and fully understand the study drug and treatment process before carrying out the test, so as to increase the subjects' confidence in completing the test. The subject should also be informed of the precautions and possible adverse drug reactions in detail to try to win the understanding and cooperation of the subject. In addition, compliance education for subjects and their families should be strengthened to make them realize the importance of following the doctor's advice.
Outcomes
Primary outcome:
The time required for a VAS score decrease ≥10 from baseline after administration.
Secondary and other outcomes:
- Changes in VAS scores from baseline at 1, 2, 4, 6, 8, 12 and 24 weeks after administration and the frequency and dosage of rescue medication;
- Comparison of the PK and PD characteristics of minodronate and alendronate in Chinese postmenopausal OP patients of different ages;
- The outcomes of PK: The concentration of minodronate and alendronate in plasma and PK parameters of minodronate and alendronate in plasma, including area under the curve (AUC0-T), peak time (Tmax), peak concentration (Cmax), half-life (T1/2), apparent clearance rate (CL), and apparent volume of distribution (V).
- The outcomes of PD:
Bone formation markers: Serum procollagen type I N-terminal propeptide (P1NP) and serum osteocalcin (OCN);
Markers of bone resorption: β-isomerized C-terminal telopeptide of type 1 collagen (β-CTX);
Markers of bone metabolism regulation: 25-OHD, parathyroid hormone (PTH);
Blood biochemical markers: blood calcium, blood phosphorus, and creatinine.
Changes in BMD (lumbar L1-L4, whole hip).
- Safety evaluation: Changes in upper gastrointestinal symptom scores from baseline at 1, 2, 4, 6, 8, 12 and 24 weeks after medication administration (e.g., heartburn, stomachache, distension).
Participant timeline:
The entire study will last 24 weeks and will be divided into two stages. The first stage is 12 weeks and will primarily focus on the relief of patients' low back pain and the incidence of gastrointestinal adverse reactions after drug administration. The second stage is 12 weeks, during which the effect of age on the quantitative relationship of BTM-BMD will be evaluated.
Sample size:
The study is an exploratory study with a small sample. According to a randomized controlled trial published in the Journal of Bone and Mineral Metabolism in 2013[11],the mean percentage change in VAS score was 49.8% for alendronate and 56.4% for minodronate at 24 weeks post-treatment. In this study, a 1:1 design method is adopted to estimate the sample size required by the T test of two independent samples, and α=0.05, 1-β=0.90, considering a 10% loss to follow-up rate. A total of 72 patients will be each required for the alendronate group and minodronate group, including 24 patients in the elderly group and 48 patients in the senior group.
Assessment of Outcomes:
VAS score: Subjective pain perception will be quantified using a VAS score. The VAS uses a straight line without any segmentation. 0 indicates no pain; less than 30 mm is defined as mild to tolerable pain; 40-60 mm is pain that affects sleep, which is tolerable; and 70-100 mm indicates that the patient has a gradual increase in pain that is unbearable and affects appetite and sleep. The patient will score their pain accordingly on the rating scale.
Izumo scale: The gastrointestinal adverse reactions caused by the oral administration of minodronate and alendronate will be recorded by the Izumo scale. The Izumo scale included 15 questions for five clinical symptoms, including heartburn, stomach pain, bloating, constipation and diarrhoea.
Pharmacokinetics: Plasma concentrations of minodronate and alendronate will be determined using the fully methodologically validated LS-MS method. The total of 2 ml of blood from the elbow vein will be collected on the 1st day (before administration), 8th week, 12th week, and 24th week. These samples will be placed in tubes containing EDTA anticoagulant and then immediately centrifuged at 2-8 °C for 10 min (1500 g). The plasma samples will be separated and frozen at -80 °C for measurement.
Bone turnover markers:8-mL of the elbow vein will be collected into a vacuum tubes without anticoagulant and sent to the laboratory for testing on the 1st day (before administration), 8th week, 12th week, and 24th week .
Bone mineral density:BMD will be measured using a dual-energy X-ray absorptiometry (DXA). The BMD will be measured for the lumbar spine (L1 to L4) and total hip. The difference and percentage change between BMD and baseline at each time point after administration will be calculated.
Data management:
The assessments will be conducted in the Outpatient Department of Peking University Third Hospital, and the intervention process will be carried out in the Peking University Third Hospital Drug Clinical Trial Center. All the assessments will be carried out by trained and experienced clinicians.
The data management department will design Case report form (CRF) based on the scheme. The investigator will complete the CRF accurately, completely, and promptly according to the original data. Raw data must remain attributable, legible, timely, and accurate. The original medical record should be complete and clear. Correction of data should be accompanied by an indication of the reason for correction, modification person, and modification date, and the modification trace should be retained. Inspectors will review the CRF and check it against the raw data to ensure its integrity and consistency. The data manager will check the data input into EDC (Microsoft Ware Excel 2019) logically to ensure the accuracy of the data. All audit trails should be kept during data management. The data manager will raise questions regarding the questionable data, all questions will be resolved, and each CRF will be electronically signed by the investigator. Sponsor leaders, researchers, data managers, and statistical analysts will review the data together. The database will be eventually locked to archive the file.
Statistical methods:
SAS and other statistical software will be used to analyse the outcomes. Quantitative data will be expressed as the mean ± standard deviation, and a T test will be used to compare the data between the 4 groups. For the comparison between groups, all hypothesis tests will be performed by a two-sided test (α=0.05, unless otherwise specified). P<0.05 will be considered statistically significant. The confidence intervals for all tests will be 95%. The comparison of general conditions between groups will be analyzed by appropriate methods according to the type of indicators. The T test, ANOVA, Wilcoxon test, or Kruskal‒Wallis test will be used for the comparison between groups of quantitative data; the chi-square test or exact probability method will be used for the comparison between groups of classified data; and Wilcoxon rank-sum tests will be used for the rank data.
Data monitoring:
The clinical trials will be monitored periodically by the sponsor or by CRO authorized by the sponsor. The supervisor confirms that the clinical trial activities will comply with the relevant regulations according to the SOP; identify clinical trial qualifications and resources; check the consistency of CRF, raw data, and other test-related materials; and write an inspection report.
Adverse events:
Oral bisphosphonate are associated with a relatively high incidence of adverse events related to the upper gastrointestinal tract, including heartburn, epigastric pain, and epigastric distention. The adverse events (AEs) will be determined using the Common Adverse Event Evaluation criteria (CTCAE V5.0). When an AE occurs, researchers should actively take appropriate measures to ensure the safety of subjects. All AEs should be followed up until the event is resolved. Event resolution is when the subject's health returns to its baseline state or when the investigator does not expect any further improvement or deterioration in the AE. If follow-up is not possible for any reason, an explanation must be provided in the subject's original medical records and case-report forms. All AEs, regardless of severity or causal association with the trial drug, will be recorded on the appropriate AE page in the subject's original medical record and case-report form from the time the subject will provide informed consent. When a sudden adverse event, such as cardiac arrest, cerebrovascular accident, or respiratory failure, will be detected, the study physicians and principal investigators will be immediately rescued according to the hospital procedures. The team should take the following measures: immediate treatment, careful observation, detailed recording, and follow-up until the AE completely disappears and the patient is in a stable condition, as well as determination of whether there is a causal relationship with the test drug.
Auditing:
Clinical trials will be audited by the quality assurance unit. The department will audit the clinical trial to evaluate whether the trial-related activities and records are in compliance with the trial protocol, SOP, and regulations related to drug clinical trials and prepare audit reports.