scholarly journals MON-LB53 Prior Injectable Somatostatin Receptor Ligand Dose Does Not Predict Oral Octreotide Response In The Treatment Of Acromegaly: Results From The Phase 3 OPTIMAL Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lisa B Nachtigall ◽  
Susan Leanne Samson ◽  
Maria Fleseriu ◽  
Marek Bolanowski ◽  
William Henry Ludlam ◽  
...  
Keyword(s):  
Treatment Effect ◽  
Low Dose ◽  
Somatostatin Receptor ◽  
Prior Treatment ◽  
High Dose ◽  
Low Doses ◽  
Phase 3 ◽  
Somatostatin Receptor Ligands ◽  
Igf I ◽  
High Doses

Abstract Background: Injectable somatostatin receptor ligands (SRLs) are the most widely used therapy to control acromegaly. Oral octreotide capsules have been formulated as a potential therapy for this disorder and the efficacy and safety was evaluated in the CHIASMA OPTIMAL prospective phase 3 study in patients with acromegaly who were controlled on injectable SRL treatment of varying doses (Samson et al. ENDO 2020). Methods: Patients with confirmed acromegaly, who had been receiving a stable dose of injectable SRL (≥3 months) up until study entry, were randomized to receive octreotide capsules (40 mg/day) or placebo for 36 weeks. Patients were dose titrated to 60 or 80 mg of oral octreotide or equivalent placebo through week 24 at the investigator’s discretion based on increase of IGF-I levels or worsening of acromegaly signs and symptoms. The primary efficacy endpoint was the proportion of patients who maintained their biochemical response at the end of 36 weeks, defined as average IGF-I ≤1 x ULN between Weeks 34 and 36. An analysis evaluated maintenance of response based on prior dose of injectable SRL. Prior doses of injectable SRL were categorized based on the following classifications: octreotide 10 mg every 4 weeks or lanreotide 60 mg every 4 weeks or 120 mg every 8 weeks were stratified as low; octreotide 20 mg every 4 weeks or lanreotide 90 mg every 4 weeks or 120 mg every 6 weeks were stratified as medium; octreotide 30 mg or 40 mg or lanreotide 120 mg every 4 weeks were stratified as high. Randomization was stratified based on low dose vs med/high dose and efficacy results compared for these strata. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Six patients (21.4%) in the octreotide capsule group had received prior treatment with low doses of injectable SRLs while 22 (78.6%) had received prior treatment with medium-high doses of injectable SRLs. Maintenance of response was observed in 16 patients receiving oral octreotide. This included 66.7% of patients (n=4) previously receiving low doses of injected SRLs and 54.5% of patients (n=12) on medium-high injected doses. The treatment effect was consistent irrespective of prior dose of injectable SRL (odds ratio: 5.4 in low dose and 5.9 in medium-high dose). Conclusion: The CHIASMA OPTIMAL study recruited a population receiving predominantly medium-high doses of injectable SRLs and demonstrated maintenance of response in 58% of patients. Oral octreotide treatment effect was consistent irrespective of prior dose of injectable SRL.

ANDROGENIZATION OF THE NEONATAL FEMALE RAT WITH VERY LOW DOSES OF ANDROGEN

1973 ◽  
Vol 57 (1) ◽  
pp. 33-45 ◽  
Author(s):  
P. J. SHERIDAN ◽  
M. X. ZARROW ◽  
V. H. DENENBERG
Keyword(s):  
Low Dose ◽  
Physiological Effect ◽  
Neonatal Rat ◽  
Female Rats ◽  
High Dose ◽  
Female Rat ◽  
Low Doses ◽  
Minimal Effective Dose ◽  
High Doses ◽  
Long Acting

SUMMARY The administration of a high dose of androgen on a single day to a neonatal female rat has been shown repeatedly to induce persistent vaginal cornification (PVC). However, this type of treatment does not parallel the continuous androgen secretion present in the male, and the high doses that have been used could represent a pharmacological and not a physiological effect. Experiments were carried out to determine the minimal effective dose of testosterone propionate (TP) needed to cause PVC when the androgen is administered to the neonatal rat for the first 10 days of life or as a long-acting ester. Injection of 1, 3 or 9 μg TP on days 1–10 of life in female rats induced PVC in adulthood. All three doses were found to be more effective than a testicular transplant on day 1. In female rats injected with low doses of TP twice daily for the first 10 days of life, PVC was shown between 90 and 100 days of life in 21 out of 22 animals given 0·5 μg TP/injection, and in eight out of 22 animals given 0·05 μg TP/injection. In an experiment where female rats were given a single injection of 0·1, 1·0 or 10·0 μg TP, or 0·1 or 1·0 μg testosterone cyclopentylpropionate (TC, a long-acting androgen) on the first day after birth, PVC occurred at 90–100 days of age in 15 of the 18 animals which were injected with 10 μg TP, in none of the 17 animals which were injected with 1 μg TP, and in 10 of 11 animals which were injected with 1 μg TC. The effects of all treatments on vaginal opening, first oestrus, ovarian weight, body weight and sexual behaviour are reported. The use and implications of low dose regimens are discussed in relation to the construction of an experimental model for the study of sexual differentiation.

scholarly journals A Phase 3 Large International Noninferiority Trial (MPOWERED): Assessing Maintenance of Response to Oral Octreotide Capsules in Comparison to Injectable Somatostatin Receptor Ligands

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A517-A517
Author(s):  
Maria Fleseriu ◽  
Alexander V Dreval ◽  
Yulia Pokramovich ◽  
Irina Bondar ◽  
Elena Isaeva ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Safety Data ◽  
Biochemical Response ◽  
Receptor Ligands ◽  
Phase 3 ◽  
Landmark Analysis ◽  
End Point ◽  
Noninferiority Trial ◽  
Somatostatin Receptor Ligands ◽  
Igf I

Abstract Background: MPOWERED, a large phase 3 trial, assessed maintenance of response to oral octreotide capsules (OOC; MYCAPSSA®) compared to injectable somatostatin receptor ligands (iSRLs) in patients with acromegaly who responded to OOC and iSRLs (octreotide or lanreotide). OOC were recently approved in the US for patients with acromegaly who responded to and tolerated iSRLs. Methods: Eligibility criteria included age 18-75 years at screening, acromegaly diagnosis, disease evidence, biochemical control (insulin-like growth factor I [IGF-I] <1.3 × upper limit of normal [ULN] and mean integrated growth hormone [GH] <2.5 ng/mL) at screening, and ≥6 months’ iSRL treatment. Effective OOC dose was determined in a 26-week Run-in phase. Eligible patients (IGF-I <1.3 × ULN and mean integrated GH <2.5 ng/mL, week 24) were randomized to a 36-week controlled treatment phase (RCT), receiving OOC or iSRLs starting at week 26. The primary end point was a noninferiority assessment of proportion of patients biochemically controlled in the RCT (IGF-I <1.3 × ULN using time-weighted average). Other end points included nonresponse imputation of the primary end point, landmark analysis using proportion of responders based on average of last 2 IGF-I values at end of RCT, and change from baseline RCT (week 26) IGF-I and GH levels. Results: Of 146 enrolled patients, 92 entered the RCT (OOC, n=55; iSRLs, n=37). Both arms were well balanced for age, sex, and acromegaly duration. OOC demonstrated noninferiority to iSRLs in maintaining biochemical response, with 91% (CI, 80%-97%) of OOC and 100% (CI, 91%-100%) of iSRL groups maintaining control during the RCT. Of those responding at end of Run-in, 96% of patients on OOC maintained response during RCT. Using nonresponse imputation, 89% of OOC and 95% of iSRL groups were biochemically controlled in RCT. Landmark analysis of those respnding at end of Run-in showed that 94% of patients in each group maintained response at RCT end. In both groups, IGF-I levels were stable in the RCT, average IGF-I at baseline and RCT end being 0.9 × ULN (OOC) and 0.8 × ULN (iSRL). Mean change in GH from RCT start to RCT end was -0.03 ng/mL (OOC) and +0.29 ng/mL (iSRL). Safety data were mostly similar between groups; the OOC group did not experience injection site reactions. Conclusion: In this noninferiority trial in patients with acromegaly, OOC demonstrated maintenance of biochemical response compared to iSRLs. Results support the efficacy of OOC as a possible iSRL alternative.

scholarly journals The Effects of Increasing Doses of Ranitidine on Gastric pH in Children

2004 ◽  
Vol 9 (4) ◽  
pp. 259-264 ◽  
Author(s):  
Seema Khan ◽  
Theresa M. Shalaby ◽  
Susan R. Orenstein
Keyword(s):  
Low Dose ◽  
Ph Monitoring ◽  
Phase 1 ◽  
Randomized Study ◽  
Gastric Ph ◽  
Fixed Dose ◽  
High Dose ◽  
Low Doses ◽  
The Mean ◽  
High Doses

BACKGROUND Ranitidine is widely used for gastroesophageal reflux disease (GERD) in children, but optimal dosing is unclear. We compared effects of weight-based doses of oral ranitidine on gastric pH in children with clinical GERD. METHODS Children ages 4–11 years with clinical GERD were enrolled in a multi-center prospective randomized study comparing a fixed dose of ranitidine (Zantac 75) with placebo after an overnight fast; gastric pH was measured for 6 h after the fixed dose (Phase 1). Of the six enrollees from our center, four received active drug during Phase 1; 12 h after the fixed dose, these four children received ranitidine 5 mg/kg (maximum 150 mg) and gastric pH was measured for another 6–12 hours (Phase 2). This report details the effects of two dose ranges (Low Dose, < 3 mg/kg/dose, and High Dose, ≥ 3 mg/kg/dose) on gastric pH in children. RESULTS The four children were 6.9–11.3 years old and weighed 20.4–49.5 kg. The Low Doses were 1.5–2.7 mg/kg; the High Doses were 3–5 mg/kg. Although the mean percentage of time with gastric pH > 4 during the entire 6 hours following dosing was similar after Low and High Dose (50% vs. 57%, NS), during the last two hours of this interval the mean percentage of time with gastric pH > 4 was only 29% for Low Dose vs. 89% for High Dose (P = 0.006). Moreover, during those two hours, none of the Low Doses kept gastric pH above 4 for > 60% of the time, while all of the High Doses kept pH above 4 for > 60% of the time (P = 0.03). In three of four patients who underwent extended (9–12 h) gastric pH monitoring after High Dose ranitidine, gastric pH was above 4 for more than 40% of total time. CONCLUSIONS Doses of ranitidine ≥ 3 mg/kg/dose may be required for acid suppression lasting beyond 6 hours.

Cost-Effectiveness and Efficacy of a Novel Combination Regimen in Acromegaly: A Prospective, Randomized Trial

2020 ◽  
Vol 105 (9) ◽  
pp. e3236-e3245 ◽  
Author(s):  
Vivien Bonert ◽  
James Mirocha ◽  
John Carmichael ◽  
Kevin C J Yuen ◽  
Takako Araki ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Combination Therapy ◽  
Low Dose ◽  
Somatostatin Receptor ◽  
High Dose ◽  
Combination Regimen ◽  
Biochemical Control ◽  
Igf I ◽  
Dose Combination ◽  
Combination Regimens

Abstract Context Combination therapy with somatostatin receptor ligand (SRL) plus pegvisomant for patients with acromegaly is recommended after a maximizing dose on monotherapy. Lower-dose combination regimens are not well studied. Objective To compare cost-effectiveness and efficacy of 3 lower-dose combination regimens in controlled and uncontrolled acromegaly Design and Setting Prospective, randomized, open-label, parallel arm study at a tertiary referral pituitary center. Patients Adults with acromegaly regardless of response to prior SRL and biochemical control status at baseline, stratified by an SRL dose required for insulin-like growth factor (IGF)-I normalization during any 3-month period within 12 months preceding enrollment. Intervention Combination therapy for 24 to 32 weeks on arm A, high-dose SRL (lanreotide 120 mg/octreotide long-acting release [LAR] 30 mg) plus weekly pegvisomant (40-160 mg/week); arm B, low-dose SRL (lanreotide 60 mg/octreotide LAR 10 mg) plus weekly pegvisomant; or arm C, low-dose SRL plus daily pegvisomant (15-60 mg/day) Main Outcome Measure Monthly treatment cost in each arm in participants completing ≥ 24 weeks of therapy. Results Sixty patients were enrolled and 52 were evaluable. Fifty of 52 (96%) demonstrated IGF-I control regardless of prior SRL responsiveness (arm A, 14/15 [93.3%]; arm B, 22/23 [95.7%]; arm C, 14/14 [100%]). Arm B was least costly (mean, $9837 ± 1375 per month), arm C was most expensive (mean, $22543 ± 11158 per month), and arm A had an intermediate cost (mean, $14261 ± 1645 per month). Approximately 30% of patients required pegvisomant dose uptitration. Rates of adverse events were all < 10%. Conclusions Low-dose SRL plus weekly pegvisomant represents a novel dosing option for achieving cost-effective, optimal biochemical control in patients with uncontrolled acromegaly requiring combination therapy.

scholarly journals Biological Control of The White Cochineal Parlatoria Blanchardi (Hemiptera - Diaspididae) by Using Coccidiphagous Ladybirds and Biopesticides in Palm Groves of The Region of Ouargla (South-East Algeria)

2021 ◽  
Vol 910 (1) ◽  
pp. 012034
Author(s):  
Benameur-Saggou Hayet ◽  
Rekia Chennouf ◽  
Gassou Insar ◽  
Kirouane Noureddine ◽  
Goui Khaoula ◽  
...  
Keyword(s):  
Biological Control ◽  
Azadirachta Indica ◽  
Low Dose ◽  
Date Palm ◽  
High Dose ◽  
Aqueous Extracts ◽  
Low Doses ◽  
Neem Extract ◽  
High Doses ◽  
Very High

Abstract The white cochineal of the date palm is a very serious pest in the palm groves of the Ouargla region (South-East Algeria). Our attempt at biological control of this pest was based on the use of two coccidiphagous ladybirds Pharoscymnus ovoideus and Pharoscymnus numidicus and aqueous extracts of two Saharan plants Solenostemma argel and Azadirachta indica with two doses in two palm groves in the Ouargla region. The results obtained are very encouraging. White cochineal infestation rates of treated plants decreased considerably especially for the high dose of two treatments. The infestation rate decreased from 52.54% to 35.49% with P.ovoideus (120 ladybirds/tree) and from 54.03% to 18.88% with Neem extract (dose 5%), to 11.01% with Argel extract (dose 7.5%). The two ladybirds and the two extracts used showed highly significant differences (P=0.000), as did the two doses used (P< 0.0001). Our control attempt also showed an efficiency that increased with the increase of the dose used. It is 0.119±0.20 with the low dose of P. ovoideus to reach an efficiency of 0.324±0.23. For the extract-based treatments, the highest efficacy was recorded with the high dose Argel (0.812±0.22). It should be noted that the low doses used for both treatments gave insignificant results compared to their controls with the high doses, which showed very high significant differences with P=0.000 for the ladybird releases and P<0.0001 for the high doses of the water extracts.

Use of single or multiple injections of FSH in embryo collection programmes in goats

1993 ◽  
Vol 5 (1) ◽  
pp. 49 ◽  
Author(s):  
PA Batt ◽  
ID Killeen ◽  
AW Cameron
Keyword(s):  
Factorial Design ◽  
Low Dose ◽  
Single Injection ◽  
Control Group ◽  
High Dose ◽  
Low Doses ◽  
Multiple Injections ◽  
Embryo Recovery ◽  
The Mean ◽  
High Doses

The yield of embryos from goats treated with single injections of FSH combined with low doses of PMSG was compared with that from goats treated with conventional superovulatory regimens based on multiple doses of FSH. In one experiment, 101 female goats were assigned to 10 groups. One group received six injections of FSH-P (FSH-P control); a second group received eight injections of Ovagen (Ovagen control). The remaining eight groups conformed to a 2x2x2 factorial design in which goats received a single injection of a low or high dose of either FSH-P or Ovagen in combination with a low or high dose of PMSG. All goats were run with harnessed, entire bucks. Ovaries were examined by laparoscopy and embryos were recovered from goats that had ovulated and been mated. The mean number of normal embryos collected per goat was significantly greater in the FSH-P control group in all except those groups treated with either low or high doses of PMSG combined with a low dose of Ovagen or a low dose of PMSG combined with a high dose of Ovagen. Most goats ovulated and ovulation rates were not significantly different from the mean of the FSH-P control, except for those treated with a low dose of FSH-P combined with either low or high doses of PMSG. Embryo recovery rates were significantly lower in groups treated with a high dose of PMSG combined with a high dose of either Ovagen or FSH-P, or with low doses of PMSG and FSH-P, than in the FSH-P control.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals MON-LB57 Impact of Imputation Method and Response Cutoffs on Results From the Phase 3 OPTIMAL Study of Oral Octreotide Capsules in Adult Patients With Acromegaly

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Susan Leanne Samson ◽  
Lisa B Nachtigall ◽  
Maria Fleseriu ◽  
Murray B Gordon ◽  
Mojca Jensterle ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Response Rate ◽  
Clinical Symptoms ◽  
Somatostatin Receptor ◽  
Study Drug ◽  
Sensitivity Analyses ◽  
Biochemical Response ◽  
Phase 3 ◽  
Somatostatin Receptor Ligands ◽  
Igf I

Abstract Objective: The phase 3 CHIASMA OPTIMAL study assessed efficacy and safety of oral octreotide capsules (OOC) in patients with acromegaly controlled on injectable somatostatin receptor ligands (SRLs). Sensitivity analyses were conducted for efficacy endpoints using two methods of imputation (i.e., the process of replacing clinical data with substitution values) to address missing data points due to some subjects reverting back to their prior injectable SRL treatment. Methods: Patients were ≥18 years of age and had evidence of active acromegaly with an average IGF-I ≤ 1.0 x ULN (utilizing the IDS iSYS assay calibrated to WHO recombinant reference standard 02/254). At baseline, patients were randomized to receive OOC or placebo for 36 weeks. The primary endpoint was proportion of patients maintaining biochemical response, defined as IGF-I ≤1.0 x ULN (2-value average at weeks 34 and 36) (Samson et al. ENDO 2020). Per study protocol, patient study discontinuations were considered non-responders regardless of clinical response at the time of discontinuation (non-response imputation). Additional exploratory analyses were performed utilizing the last observation carried forward (LOCF) analysis, as well as a completers analysis of response among the subgroup that completed the entire 36 weeks on study drug. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Twenty-eight patients received OOC and 12 failed to maintain biochemical response based on the primary endpoint. Seven of these 12 patients discontinued treatment early - 5 due to treatment failure and 2 due to AEs. The remaining 5 patients completed the 36-week protocol on study drug. Of these 5 patients, 4 had IGF-I values between &gt;1.0 and ≤1.3 x ULN and 1 completed the study with an IGF-I of 1.7 x ULN with no clinical symptoms. 58.2% of patients in the OOC group met the primary endpoint of maintenance of biochemical response at the end of study using the non-response imputation. Using LOCF imputation, 64.3% (18/28) of patients met this endpoint. Of those completing the study (N=21), 76.2% maintained response. Conclusion: CHIASMA OPTIMAL primary endpoint was assessed using the non-response imputation for patients who discontinued treatment early, with a 58.2% response rate. However, when assessing the response rate based on LOCF imputation, or in study completers, similar to other phase 3 studies for acromegaly, the rate was imputed at 64.3% and 76.2%, respectively.

scholarly journals Evaluation of the BDNF, NGF, NT3 and NT4 Genes Expressions in the Brains of Neonatal Mice with Hypothyroidism

2017 ◽  
Vol 7 (1) ◽  
pp. 171
Author(s):  
Hamid Reza Adeli Bhroz ◽  
Kazem Parivar ◽  
Iraj Amiri ◽  
Nasim Hayati Roodbari
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Pure Water ◽  
Intervention Group ◽  
Control Group ◽  
High Dose ◽  
Endocrine Glands ◽  
Blood Samples ◽  
High Doses ◽  
The Brain

Background and Aim: Thyroid is one of the endocrine glands, (T3 and T4) play a significant role in the development of prenatal brain and the following stages. The study aimed to evaluate the effect of hypothyroidism on the amount of expression of NT4, NT3, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in brain of one-day rat neonates with hypothyroidism.Materials and Methods: In total, 25 mature mice of Albino NMRI race were selected after mating, divided into three group, control, as well as low-dose and high-dose intervention groups. Samples of the control group received pure water during pregnancy, whereas subjects of the intervention group with low and high doses of the medication were administered with 20 mg and 100 mg methimazole powder (dissolved in 100 cc water), respectively. After child delivery, blood samples were obtained from mother mice to determine the level of T3 and T4 in blood serum. Following that, the brain of one-day mice were removed by surgery and assessed to determine the amount of expression of NT4, NT3, NGF and BDNF using the complete kit of RT-PCR.Results: Levels of T4 and T3 in the control group were 28 ug/dl and 1.59 ug/dl, respectively. In the low-dose intervention group, the amounts of the mentioned hormones were 8 ug/dl and 0.85 ug/dl, significantly, indicating a significant reduction in the expression of NT4, NT3, NGF and BDNF genes, compared to the control group. Moreover, T4 and T3 were 6 ug/dl and 0.79 ug/dl in the high-dose group, respectively, conveying a significant decrease in the expression of NT4, NT3, NGF and BDNF genes, compared to the control group (P<0.05).

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