Clinical Trial of Infant Formula-fed
Condition: Body Weight Changes
MeSH terms: Body Weight; Body Weight Changes
Study type: Interventional

Summary: 
      Compared with breast milk and another commercially available formula, infants' growth rate
      after 12 weeks' Friso formula with low glycation feeding will be assessed.
    

Detailed description: 
      1. Sample size：Seventy two cases will be enrolled in breast milk group, 144 cases in
           formula milk group, 72 cases each in commercially available formula subgroup and Friso
           formula subgroup with 36 cases each in every hospital (18 males and 18 females).

        2. Observation period：Observational period will maintain 12 weeks. Infants of breast milk
           group are fed with breast milk before inclusion and during the trial process. In the
           formula milk groups, if subjects were fed with other formula instead of commercially
           available formula and Friso formula before inclusion, then a wash-out period of no more
           than 2 weeks is necessary.

        3. Random method: In commercially available formula subgroup and Friso formula subgroup,
           infants will be included randomly. Random allocation sequence is generated in six trial
           centers by the editorial department of Chinese Journal of Evidence-Based Pediatrics,
           included infants are chosen and their information including name, gender, their parents'
           name and telephone is reported to the editorial department of Chinese Journal of
           Evidence-Based Pediatrics via WeChat. Then group division information is acquired, the
           tested commercially available formula and Friso formula are given out to infants
           accordingly.

        4. Match of the breast milk group: Infants with purely breast milk-fed will be chosen.
           Infants'gender and body weight (±5%) of breast matched with milk-fed group commercially
           available formula subgroup and Friso formula subgroup.

        5. Blinding method: Subjects, doctors and nurses know which formula is given. Personals in
           charge of assessing stool character and ery secretion, and data analysis, are blind to
           the information of group division.

        6. Data records, monitoring and management 6.1 Data records 6.1.1 Original records:
           Subjects' follow-up care cards are original files in this clinical trial which is in
           duplicate copies. One copy should be saved in hospital. Original records shall be
           traceable. Each researcher must strictly follow the principle of GCP and ensure that he
           will record any observation and discovery in the follow-up care card and case report
           form (CRF), all data are consistent, no optional changes are allowed. If any correction
           is needed, the original record must not be changed, researchers can only add extra
           descriptions and explain the reason, the correction needs to be signed and dated by
           researchers who make it.

           6.1.2 Case report form(CRF): Each in triplicate, it will be delivered to sponsors, main
           institutions of clinical research and participating institutions of clinical research.
           According to the principle of GCP, subjects' name should not appear in order to ensure
           their privacy. Subjects' name must be filled in the initials.

           All of the choices"□" will be marked"×". If some inspection items are not examined or
           missed for some reason, it should be filled in: not examined. If the specific formula
           dosage is unknown, it should be filled in: unknown. When filled in the numbers, it
           should be filled in all □. If digits are not enough, it should be filled on right side.
           If left side is empty, it should be filled by 0. No null terms or missing items are
           allowed. Researchers must ensure that all data must be consistent with the original
           record.

           If modifying, researchers should draw a horizontal line in the middle of the original
           record text, sidenote to modify, and then sign the modifier's name and the date. He must
           not smear or cover the original record.

           6.1.3 Data Record of subjects' guardian: It should be recorded according to the items
           and their definitions in the designed CRF chart.

           6.1.4 Extremum principles: The data, deviating significantly or outside the acceptable
           range clinically, must be verified. Clinical doctors must make the necessary
           instructions.

           6.1.5 Data registration and preservation: Every time after the follow-up visit,
           researchers should record the required information in the case report sheet timely.
           After the end of each subjects' observed period, researchers should accurately record
           relevant information from original records in the form of data in the CRF within 7 days.
           CRF, informed consent and other documents should be examined and signed by the project
           leader, then saved in the archive office of institution. If a problem is found, it
           should be timely dealt with and recorded.

           6.2 Data monitoring Editorial Board of Chinese Journal of Evidence-Based Pediatrics will
           be in charge of data monitoring of the clinical trial. CJEBP will provide data
           monitoring of the clinical trial to FrieslandCampina regularly in at middle experiment
           stage and later experiment stage. During the trial, CJEBP will investigate 6 research
           centers for their quality of practice at least one time, without any announcement in
           advance. The monitoring subjects include child care doctors, nurses and guardians of
           subjects enrolled in this trial.

           6.2.1 Child care doctors: monitor the quality of explaining the research to subjects'
           guardians and the informed consent signing; Random of distribution; The accurate
           measurement of body length, weight and head-circumference; judgement of gut intolerance;
           record of stool frequency, pictures of stools and eye secretions.

           6.2.2 Nurses: motor the accuracy of the measuring equipment; the correctness of the
           measuring method; the rightness of data recording (mean value of 2 measurements); the
           management of trial formula (reception time, check-up, distribution subjects, date and
           signature, recycling subjects, date, quantity of the rest formula and signature).

           6.2.3 Guardians of subjects enrolled in this trial: randomly inspect 1-2 guardians,
           investigate whether mixed feeding or mixed with other brand formula feeding exists; the
           usage of trial formula; regularity of follow-up visits; taking photos of fresh stools
           and eye secretions.

           6.3 Data management 6.3.1 Buildup, test and data entry of WeChat client: According to
           the project of the CRF，administrators will establish WeChat client, test and modify this
           client, and enter data after ensuring the accuracy of this client. Every researcher in
           each hospital uploads the measured data to administrators by WeChat client on the day he
           completes one case observation and measurement. In order to ensure the accuracy of the
           data, administrators should compare data uploaded by WeChat client with the original
           CRF. Subjects' guardians will upload photos of stool character and eye secretion to
           administrators by WeChat client at 3 points of follow-up time.

           6.3.2 Generation and correction of doubt, quality control(QC) and database shutdown:
           After completing data input and comparison, data administrators will verify the
           reliability, integrity and accuracy of data according to requirements of clinical trial
           scheme. If he finds loss of content or logic contradiction or filling in wrong or
           uncertain data, clinical monitors will send it to clinical trial centers in the form of
           data question table (DQF). Researchers will give answers to questions as soon as
           possible and reply. Data administrators will modify, confirm and correct data according
           to researchers' answers. After solving all of problems, quality control personnels will
           check the quality of database according to QC plan. Then he will close the database
           after check.

           6.3.3 Data check, lock and transmit blindly: Data administrators submit data management
           reports, and require a meeting about data-check blindly attended by principal
           investigator, statistical analyst, data administrators, monitors, and sponsors. Check
           data blindly, sign blindly data-check resolution after meeting, lock in the database;
           locked data will be analyzed by personnels of statistical analysis.

        7. Statistic analysis 7.1 General principles: All of the statistical tests must be
           two-sided tests, P<0.05 is considered to be statistically significant difference for all
           tests. Mean, median, standard deviation, maximum, minimum, 25% and 75% quintile are used
           for statistical description of measurement data. Count data or level data is described
           by frequency ( percentage).

           SAS9.1.3 statistical software is used for statistical analysis. 7.2 Analysis of missing
           cases: List cases number of inclusion, completion and falling off. Loss rate and
           comparison between groups should be analyzed by Chi-square test and Fisher's exact
           probability method.

           7.3 Evaluation of effectiveness: Measurement data of indexes(Growth rate of height,
           weight and head circumference at 4,8,12 week, defication frequency) should be analyzed
           by normality test firstly. If data conforms to normal distribution, the comparation
           between formula milk group (commercially available formula subgroup and Friso formula
           subgroup) and breast milk group should be analysed by One-Way ANOVA method. LSD method
           is used for multiple comparisons. If data does not conform to normal distribution, then
           Wilcoxon Rank-Sum test is used. A level of significance is α=0.05 (two-tailed).
           Frequency data of indexes ( incidence of constipation at 4,8,12 week, eyes secretion) is
           recorded as cases or percentage. If theoretical frequency <5 or total observed frequency
           <30, Fisher's exact probability method is used; otherwise Chi-square test is used. A
           level of significance is α=0.05 (two-tailed).

        8. Quality control Standardized operation procedures should be established in all of
           research process.

           8.1 Qualification of research institution: Research institution must be community health
           service centers qualified for baby healthy check-up.

           8.2 Qualification of researchers: The researchers need GCP training and work under the
           guidance of senior professionals.

           8.3 Trial quality control measures: ①Before the start of clinical trials, researchers
           (including nurses) must receive training for measurement of height, weight and head
           circumference; ②check measurement bed before measurement everyday. Researchers must
           compare scale on plastic flexible rule with that on standard steel rule and change
           plastic flexible if error >0.1cm. ③The pictures of the feces and eyes will be
           independently scored by 2 specialists under the condition of unknowing the group. ④The
           specialist must be responsible for experimental formula, counter locked, storage at room
           temperature away from light. The remaining experimental formula will be stored
           separately, registering number. At the end of trial, the remaining experimental formula
           will be sent back to sponsor.⑤Monitor: Monitor will be appointed by sponsor, ensuring
           subjects' interests during period of trial. Trial record and data report must be true,
           accurate, complete and correct, ensuring that trial must comply with both approved plan
           and Relevant laws.

        9. Definition and management of adverse events 9.1 Definition of adverse events: adverse
           events are defined as those occur after a patient or a subject in a clinical study
           receives a tested product, the event does not necessarily have a causal relationship
           with the test products. Adverse events are the diseases or signs or symptoms that occur
           during the course of the study (including abnormal laboratory findings). Adverse events
           can be serious or not serious, may or may not cause the subjects to withdraw from the
           study. All adverse events must be recorded, and the relationship between the product and
           the product is evaluated.

      9.2 Information collection of adverse events: researchers must know and record the following
      information concerning adverse events: subjects and date, description of the event, source of
      report, the suspected products, continuous time, frequency, extent, severity, measures taken,
      results and complications, the relationship with tested products.

      9.3 Extent of adverse events: Mild: symptoms were not obvious, only slightly harmful to
      health. Middle: the symptoms are obvious, but can be tolerated, without immediate treatment.
      Serious: it is hard to bear.

      9.4 Severity of adverse events: Serious adverse events refer to the follwing adverse events
      which appear at any of the dosage: leading to death, threatening life , need to be
      hospitalized or hospitalization has been prolonged, resulting in permanent or significant
      disability and loss of function, congenital anomalies or birth defects, or other significant
      medical events. Not serious: Those events can not be defined as serious adverse events are
      not serious events.

      9.5 Unexpected or expected serious adverse events: Researchers must assess whether the
      adverse events be expected to occur or not. Expectation is evaluated by Safety Officer
      Medical which base on the current knowledge and existing product information. An unexpected
      adverse event is one that the nature, severity, frequency are inconsistent with conditions of
      the study and ( or) product information.

      All suspected adverse events related to the tested products, as well as serious adverse
      events that are not expected to be serious are considered to be SUSARs (suspicious unexpected
      serious adverse event). SUSAR need to be reported to the management authority or independent
      ethics committee in a very short time.

      According to the Chinese food and Drug Administration report of adverse reactions and and
      regulations of drug supervision, any new or serious adverse reactions of any drug must be
      reported within 15 days, any deaths must be reported immediately. Fax: +86-10-67184591,
      Email: report@adr.gov.cn.

      9.6 Relationship with the tested product: Medical institutions will evaluate the relationship
      between adverse events and the tested product according to the following standards. ①
      unrelevant: there is evidence proving that adverse events are caused by other reasons. For
      example, adverse events are obviously caused by the disease, adverse events are consistant
      with effects or adverse reactions of the drugs, or adverse events had already existed before
      using the tested product research. ② Not likely to be relevant: it seems to have a
      time-relationship with the use of tested product, but the occurrence of adverse events can be
      explained by other reasons. ③Probably relevant: it seems to have a time-relationship with the
      use of tested product, and adverse events seem to have a causal relationship with the
      product. ④ Surely relevant: it seems to have a time-relationship with the use of tested
      product, and no other reasons can explain the occurrence of adverse events. Adverse events
      diminish or disappear after stopping using tested products, and symptoms occur once again
      with the use of tested products.

      9.7 report and record: ①serious adverse events: clinical safety management must be informed
      by fax or scaning within 24 hours, regardless of whether the event is related to the tested
      product. When it's the first time to report, or each time when SAE needs modification,
      researchers need to complete serious adverse events spreadsheet in the eCRF, The spreadsheet
      will be automaticly sent to clinical safety manager xt211311@aliyun.com in the form of email.
      All serious adverse events are also required in the eCRF spreadsheet severity column to
      choose "serious". ②Not serious adverse events: all not serious adverse events must be
      recorded on the eCRF's adverse events page.

      9.8 follow-up visits: All serious adverse events should be followed up until the outcome of
      the event. The researchers need to inform the clinical safety manager of any follow-up
      information within 24 hours, such as changes in diagnosis, results, the date of remission,
      the termination of treatment, and so on.

      If serious adverse events persist after discontinuation of the study, follow-up is required.
      In addition, when adverse events occur, if it's necessary to further evaluate the causal
      relationship between adverse events and the tested product, then all the examinations and
      laboratory results must be recorded in the case report form or attached document. Within 30
      days after the last use of the study product, the SAE also needs to be reported in the same
      way within 24 hours.

      9.9 Inform: The sponsor is responsible for the safety evaluation of the tested product. The
      sponsor must promptly inform all researchers, observational hospitals and regulatory
      authorities of any discoveries that are likely to affect subjects' safety, influence study
      process, change the ethics committee's attitude to approve or agree that research continues.

      9.10 Report: The sponsor must accelerate reporting to all investigators, observational
      hospitals, IRB (S) /IEC (s) and management authorities (if necessary) about all serious and
      suspicious unexpected serious adverse reactions (SUSAR).

      This accelerated report needs to comply with applicable regulatory requirements, and ICH
      guidelines on the management of clinical safety data: standards of accelerated reporting.

      The sponsor should submit all latest progress and staged reports of security to management
      authorities, according to applicable regulatory requirements
    

Intervention name(s): Low glycation formula feeding; Commercially common formula feeding
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Formula feeding on demand for 3 months; Formula feeding on demand for 3 months
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Supportive Care
Keywords: Infant; Growth; Body Weight Changes; Infant Formula; Randomized Controlled Trial