Application Research of Hydromorphinone Sustained-release Tablets in the Treatment of Elderly Patients With Cancer Pain Accompanied by Renal Insufficiency
Conditions: Cancer Pain, Renal Insufficiency Chronic, Hydromorphone Use
Sponsor: Taian Cancer Hospital

Study Protocol and Statistical Analysis Plan
Study Title：Application Research of Hydromorphinone
Sustained-release Tablets in the Treatment of Elderly Patients With
Cancer Pain Accompanied by Renal Insufficiency
Study ID：YXH2025JS126
Ethics Approval Number：2025022
Document Date：2025-09-24
NCT Number：[To be assigned]
Sponsor Institution：Tai'an Cancer Hospital
Study Protocol
1.Background and Objectives
1.1 Study Background
With the aging of the population, the proportion of elderly patients with moderate to
severe cancer pain complicated with renal insufficiency has increased significantly.
First-line opioids (morphine, oxycodone) have problems
such as neurotoxic
accumulation and high incidence of gastrointestinal adverse reactions, leading to a
dilemma between "effective analgesia" and "safe medication" in clinical practice.
Domestic hydromorphone sustained-release tablets (Ruining®) have pharmacokinetic
advantages (independent of CYP450 enzyme metabolism, few active metabolites,
non-renal dominant metabolism), but there is a lack of prospective clinical evidence
in elderly cancer pain patients with renal insufficiency. Its efficacy, renal safety and
the risk of opioid-induced neurotoxicity (OIN) need to be clarified urgently.
1.2 Study Objectives
To systematically evaluate the analgesic efficacy and clinical safety of domestic
hydromorphone sustained-release tablets in elderly patients (≥65 years old) with
moderate to severe cancer pain and renal insufficiency;
To focus on observing the dynamic changes of estimated glomerular filtration rate
(eGFR) and the occurrence of OIN after medication;
To explore and construct an OIN risk prediction model to provide an individualized
medication guide for this special population.
2. Study Design
Study Type：Prospective, single-center, non-randomized cohort study
Sample Size ：62 patients, divided into 2 groups: Hydromorphone - Renal
Insufficiency Group and Hydromorphone - Normal Renal Function Group.
Study Site：Department of Medical Oncology, Tai'an Cancer Hospital
Study Period：4 weeks of follow-up after enrollment (7-day titration period + 21-day
maintenance period)

3 .Study Population
3.1 Inclusion Criteria
1）Age ≥65 years.
2）Pathologically or cytologically confirmed malignant tumor.
3）Opioid-naïve patients with moderate-to-severe cancer pain (Numerical Rating Scale
score ≥4).
4)
Renal
function
meeting
one
of
the
following
criteria
at
baseline:1 ）
Mild-to-moderate
renal
insufficiency
group:
30
mL/min/1.73m²
≤
estimated
glomerular filtration rate (eGFR) < 90 mL/min/1.73m².2）Normal renal function group:
eGFR ≥90 mL/min/1.73m².
5) Expected survival period ≥3 months.
6) Ability to take oral medication and cooperate with study assessments.
7) Willing to participate voluntarily and able to provide signed informed consent.
3.2 Exclusion Criteria:
1) Severe renal insufficiency (eGFR < 30 mL/min/1.73m²) or requirement for renal
replacement therapy.
2) Severe hepatic insufficiency (alanine aminotransferase / aspartate aminotransferase
≥2.5 times the upper limit of normal or Child-Pugh Class C).
3) Paralytic ileus.
4) Pain of unclear origin or pain that is solely acute/incident pain.
5) Symptoms or history of diseases such as intracranial hypertension, head injury,
cerebral aneurysm, or other central nervous system disorders.
6)
Symptoms
of
prostatic
hypertrophy,
thyroid
dysfunction,
or
urethral
stricture.Symptoms of asthma, respiratory obstruction, or respiratory failure.
7) Known allergy or hypersensitivity to hydromorphone or oxycodone.
8) Use of monoamine oxidase inhibitors within 14 days prior to enrollment.
9) Participation in any other clinical trial within 1 month prior to enrollment.
10) Any other condition considered by the investigator as unsuitable for participation
in this study.
4 .Treatment Regimen
A standardized titration and maintenance regimen was formulated with reference to
the NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain (2025
Version), using domestic hydromorphone sustained-release tablets (Ruining®)
throughout the study, divided into titration period (D1-D7) and maintenance period
(D8 to the 4th weekend).
4.1 Titration Period (D1-D7)
D1: Initially administer hydromorphone injection 0.5mg subcutaneously, and assess
pain 30 minutes later:
Ineffective/aggravated pain: increase the next dose by 50%;
Improved but insufficiently controlled pain: keep the titration dose unchanged;
Sufficiently controlled pain: titrate on demand according to the current dose within 24
hours.
Reassess patients with uncontrolled pain after 2-3 rounds of titration; for patients with
stable pain, convert the total daily dose of hydromorphone injection in 24 hours to the

equivalent daily dose of oral hydromorphone sustained-release tablets, round down to
the whole tablet specification, and administer orally once a day from the next day.
D2-D7: Background medication with sustained-release tablets, rescue treatment for
breakthrough pain with hydromorphone injection (dose: 10% of the oral morphine
equivalent daily dose (OMEDD) in the previous 24 hours); if the average number of
rescue medications for breakthrough pain is ≤3 times/day from D4, maintain the
current dose; if >3 times/day, recalculate the dose and round down to the whole tablet.
4.2 Maintenance Period (D8 to the 4th weekend)
Administer hydromorphone sustained-release tablets orally once a day according to
the dose determined in the titration period; if the number of breakthrough pain ≥3
times/day, optimize the dose according to the titration period method. Follow up once
a week to record the medication dose, number of breakthrough pain, adverse reactions,
etc.
4.3 Renal Function and Safety Monitoring
Renal function test: detect serum creatinine at baseline, D7, and the 2nd/3rd/4th
weekend, and calculate eGFR;
Special OIN assessment: evaluate OIN manifestations such as delirium, somnolence,
myoclonus and hallucination weekly using the Confusion Assessment Method (CAM),
Epworth Sleepiness Scale (ESS), Myoclonus Grading Scale, and Brief Psychiatric
Rating Scale (BPRS);
General adverse reactions: record nausea, vomiting, constipation, hypertension,
respiratory depression, etc. according to CTCAE Version 5.0 grading.
5 . Outcome Measures
5.1 Primary Outcome Measures
Primary safety endpoint: Change in eGFR at the 4th weekend of treatment compared
with baseline;
Primary efficacy endpoint: Pain relief rate on the 7th day of treatment (proportion of
patients with NRS ≤3 points).
5.2 Secondary Outcome Measures
Efficacy measures: Time to reach stable analgesia, change in NRS score at each
follow-up point, number of 24-hour breakthrough pain, consumption of rescue drugs,
Sun Yan's Quality of Life (QOL) score, Brief Pain Inventory (BPI) score, Patient
Global Impression of Change (PGIC) score;
Safety measures: Dynamic change trend of eGFR, overall incidence of adverse
reactions, incidence and grading of OIN, incidence of abnormal liver and renal
function.
5.3 Exploratory Outcome Measure
If the number of OIN cases ≥20, a nomogram model for OIN risk prediction based on
multivariate Logistic regression will be constructed to analyze risk factors such as age,
baseline eGFR, stable dose of hydromorphone, and combined medication.
6. Statistical Analysis Plan
Statistical Software: SPSS 26.0, R 4.5.0
Descriptive Analysis: Normally distributed measurement data are expressed as (xˉ±s),
non-normal data as M (Q1-Q3); count data as n (%);

Baseline Balance Comparison: Independent sample t-test/Mann-Whitney U test for
continuous variables, χ² test/Fisher's exact test for categorical variables;
Primary Outcome Analysis: Analysis of covariance (ANCOVA) for eGFR change
(with baseline eGFR as a covariate); χ² test for pain relief rate;
Repeated Measurement Data: Generalized Estimating Equations (GEE) for NRS score
and number of breakthrough pain; Linear Mixed Model (LMM) for dynamic changes
of eGFR;
Survival Analysis: Kaplan-Meier method + Log-rank test for time to reach stable
analgesia;
Model Construction: Multivariate Logistic regression for OIN risk prediction, internal
validation by Bootstrap method (1000 resamplings), and ROC curve, calibration curve
and Decision Curve Analysis (DCA) to evaluate the model;
Missing Data Handling: Complete case analysis as the main method, multiple
imputation for missing data <20%, and deletion for missing data ≥20%.
7. Principles of Adverse Reaction Management
Grade 3 or above adverse reactions: Suspend medication, conduct multidisciplinary
consultation within 24 hours, and provide symptomatic treatment (e.g., naloxone for
respiratory depression);
Moderate to severe OIN: Switch to fentanyl transdermal patch (25μg/h initial dose),
and symptomatic treatment with clonazepam 0.5mg bid;
Grade 1-2 adverse reactions: Preventive intervention (e.g., metoclopramide for
antiemesis, lactulose for laxation);
Management of acute renal function deterioration: If eGFR decreases by more than
30% from baseline or drops to <30 mL/min/1.73m², immediately suspend the study
medication and invite the nephrology department for emergency consultation and
disposal.
Informed Consent Form
Cover Page
Official Title：Application Research of Hydromorphinone Sustained-release
Tablets in the Treatment of Elderly Patients With Cancer Pain Accompanied by
Renal Insufficiency
InsufficiencyStudy ID：YXH2025JS126
Ethics Approval Number：2025022
Document Type：Informed Consent Form
Document Date：2025-09-24
NCT Number：[To be assigned]
Sponsor Institution：Tai'an Cancer Hospital

Dear Patient and Family Members:
We are conducting a clinical study funded by the Shandong Medical Association to
evaluate the efficacy and safety of hydromorphone sustained-release tablets in elderly
cancer pain patients with or without renal insufficiency, so as to provide evidence for
clinical safe medication. This study has been approved by the Ethics Committee of
Tai'an Cancer Hospital, and we now invite you to participate in this study. Please read
the following content carefully, consult the study physicians if you have any questions,
and decide whether to participate voluntarily after full understanding.
1. Study Purpose
To evaluate the analgesic efficacy of domestic hydromorphone sustained-release
tablets in elderly patients (≥65 years old) with moderate to severe cancer pain (with or
without renal insufficiency), observe the changes of renal function and adverse
reactions such as neurotoxicity after medication, and provide evidence for formulating
individualized medication plans for this population.
2 .Study Drug and Treatment Plan
The study drug is Hydromorphone Sustained-Release Tablets (Ruining®), an opioid
analgesic approved for marketing in China, suitable for moderate to severe cancer
pain.The treatment is divided into 2 stages: ①Titration period (7 days): first titrate
pain
with
hydromorphone
injection,
and
convert
to
oral
hydromorphone
sustained-release tablets after stability; ②Maintenance period (21 days): take
sustained-release tablets orally once a day, and adjust the dose according to pain
conditions. The medication plan will be formulated by specialist doctors throughout
the study, and pain assessment and liver and kidney function tests related to the study
will be provided for you free of charge.
3 .Study Flow
If you meet the enrollment criteria and sign this consent form, you will complete the
following study flow:
Baseline assessment: complete pathological examination, pain score (NRS), liver and
kidney function, cognitive function assessment, and sign the informed consent form;
Treatment and follow-up: receive drug treatment according to the plan, follow up in
the hospital once a week, complete pain assessment, liver and kidney function tests
and adverse reaction records, the total follow-up time of the study is 4 weeks;
Final follow-up: after the study, the doctor will formulate a follow-up routine
analgesic treatment plan according to your condition.
4. Your Rights
Participation in this study is voluntary, and you can withdraw unconditionally at any
stage of the study without affecting your routine diagnosis and treatment and
doctor-patient relationship;
The costs of study-related examinations (liver and kidney function, pain assessment,
etc.) are borne by the research fund, and you do not need to pay;
Your personal information (name, ID number, medical records, etc.) will be strictly
confidential and only used for statistical analysis of this study. Personal information
will be concealed when the research results are published;

You have the right to consult the study physicians about the study at any time and get
timely and professional answers.
5. Your Obligations
Take medication strictly according to the plan formulated by the doctor, and do not
increase/decrease the dose, stop or replace the drug without permission;
Complete all follow-up examinations on time, and contact the study physicians in
time if you experience aggravated pain, dizziness, somnolence, nausea, vomiting and
other discomfort;
Truthfully inform the study physicians of your medication history, allergy history and
physical discomfort, and cooperate to complete various assessments and records.
6 .Potential Benefits and Risks
6.1 Potential Benefits
Obtain an individualized cancer pain analgesic plan formulated by a specialist doctor
to control pain more accurately and safely and improve the quality of life;
Complete study-related examinations such as pain assessment and liver and kidney
function tests free of charge during the study, saving medical expenses;
The research results will provide evidence for the safe medication of elderly cancer
pain patients, benefiting more patients.
6.2 Potential Risks
Common adverse reactions of opioids: nausea, vomiting, constipation, dizziness,
somnolence, etc., most of which are mild to moderate. The doctor will take preventive
measures in advance (such as antiemetic and laxative drugs), and adjust the
medication plan in time if severe discomfort occurs;
Rare severe adverse reactions: opioid-induced neurotoxicity (delirium, myoclonus),
respiratory depression, transient renal insufficiency, etc. The research team has
formulated a standardized emergency treatment plan, and a multidisciplinary
consultation will be initiated immediately once they occur to ensure your safety;
If your pain is not effectively controlled during the titration period, the doctor will
replace it with other analgesic drugs in time to ensure the effect of your pain
treatment.
7 .Privacy Protection
All your study-related records are kept by a special person in Tai'an Cancer Hospital,
with an encrypted database accessible only to the research team. Your personal
identity information will not be disclosed during the study and in the publication of
research results, in line with the Declaration of Helsinki and domestic medical ethical
norms.
8. Consultation Method
If you have any questions, discomfort or suggestions during the study, please go to the
Department of Medical Oncology, Tai'an Cancer Hospital to consult the study
physicians in time, or call the department consultation hotline: +86 0538-2066855.
9 .Consent Statement
I have carefully read and understood all the contents of this informed consent form.
The study physicians have given me a detailed explanation of the study-related issues.
I voluntarily participate in this study, am aware of the benefits and risks of the study,

and agree to cooperate to complete all study procedures. This consent form is in two
copies, one for the patient/family member and one for the research institution, with
the same legal effect.
Patient's Signature：____________________
ID Number：____________________
Date：____//__
Family Member's Signature (if the patient cannot sign by himself/herself)：
____________________
Relationship with the Patient：____________________
Date：____//__
Study Physician's Signature：____________________
Title：____________________
Date：____//__